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BACKGROUND Despite the widespread use of botulinum toxin (BTX) injection for the treatment of masseter muscle hypertrophy (MMH), there is no standard treatment option. OBJECTIVE We report the efficacy and safety for BTX in MMH over a period of 48 weeks. METHODS In double-blinded, placebo-controlled phase 3 trials, 180 patients (randomized 1:1) received treatment with placebo (normal saline) or prabotulinumtoxinA (48 units). Masseter muscle thickness (at maximal clenching and resting positions), 3D imaging analysis, and masseter muscle hypertrophy scale grades were analyzed at each time point. After the 24-week CORE study, all patients who met the same criteria of the CORE study at week 24 (n 5 114) received only prabotulinumtoxinA, regardless of previous treatment, for an additional 24 weeks (48 weeks in total) for the open-label extension study. RESULTS The largest differences in mean and percent changes from baseline in masseter muscle thickness were observed at 12 weeks, and there were significant differences between the 2 groups at all time points (all p, .001). The effect was independent of the number of injections. No serious adverse event was observed. CONCLUSION PrabotulinumtoxinA could effectively ameliorate MMH without major complications. [ABSTRACT FROM AUTHOR]

Natural physique athletes strive to achieve low body fat levels while promoting muscle mass hypertrophy for competition day. This study aimed to compare the anthropometric characteristics of natural amateur (AMA) and professional (PRO) World Natural Bodybuilding Federation (WNBF) competitors. Eleven male natural physique athletes (6 PRO and 5 AMA; age = 24.8 ± 2.3 years) underwent a comprehensive anthropometric evaluation following the International Society for the Advancement of Kinanthropometry protocol within a 24-hour time frame surrounding the competition. The 5-component fractionation method was used to obtain the body composition profile of the muscle, adipose, bone, skin, and residual tissues. Five physique athletes exceeded the 5.2 cutoff point of muscle-to-bone ratio (MBR) for natural athletes. Professional physique athletes were older than AMA physique athletes (p = 0.05), and they also presented larger thigh girths (p = 0.005) and bone mass (p = 0.019) compared with AMA physique athletes. Although no statistically significant between-group differences were observed in body mass, height, or body fat levels, PRO physique athletes exhibited a higher body mass index (BMI; AMA: 24.45 ± 0.12; PRO: 25.52 ± 1.01; p = 0.048), lean body mass (LBM; AMA: 64.49 ± 2.35; PRO: 69.80 ± 3.78; p = 0.024), fat-free mass (FFM; AMA: 71.23 ± 3.21; PRO: 76.52 ± 4.31; p = 0.05), LBM index (LBMI; AMA: 20.65 ± 0.52; PRO: 21.74 ± 0.85; p = 0.034), and fat-free mass index index (FFMI; AMA: 22.80 ± 0.22; PRO: 23.83 ± 0.90; p = 0.037) compared with AMA physique athletes. These findings highlight the unique characteristics and anthropometric differences between PRO and AMA natural physique athletes on competition day, emphasizing the significance of age, thigh girth, bone mass, BMI, LBM, FFM, and FFMI in distinguishing these 2 groups. Based on our findings, the established boundaries for muscle mass in natural physique athletes, based on FFMI and MBR, warrant reconsideration. [ABSTRACT FROM AUTHOR]

Purpose: Neuromuscular deficits and atrophy after anterior cruciate ligament reconstruction (ACLR) may be accompanied by changes in muscle composition and poor quadriceps muscle quality (QMQ). Quadriceps atrophy occurs after ACLR but improves within the first three postoperative months, yet this hypertrophy could be attributable to increases in noncontractile tissue (i.e., poor QMQ). The purposes of this study were to evaluate changes in QMQ after ACLR and to determine if changes in QMQ and cross-sectional area (CSA) occur in parallel or independently. Methods: A longitudinal prospective cohort design was implemented to evaluate QMQ and CSA in 20 individuals with ACLR and 12 healthy controls. Participants completed three testing sessions (baseline/presurgery, 1 month, and 3 months) during which ultrasound images were obtained from the vastus lateralis (VL) and rectus femoris (RF). QMQ was calculated as the echo intensity (EI) of each image, with high EI representing poorer QMQ. Anatomical CSA was also obtained from each image. Results: RF and VL EI were greater at 1 and 3 months in the ACLR limb compared with baseline and the contralateral limb and did not change between 1 and 3 months. VL and RF CSA in the ACLR limb were smaller at 1 and 3 months compared with the contralateral limb and controls (VL only) but increased from 1 to 3 months. Changes in QMQ and CSA were not correlated. Conclusions: QMQ declines within the first month after ACLR and does not improve by 3 months although hypertrophy occurs, suggesting that these morphological characteristics change independently after ACLR. Poorer QMQ represents greater concentration of noncontractile tissues within the muscle and potentially contributes to chronic quadriceps dysfunction observed after ACLR. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2 -knockdown zebrafish, and Fars2 -knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2 -deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2 R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2 -knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNAPhe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy. [ABSTRACT FROM AUTHOR]

To systematically review and analyze the effects of resistance-based exercise programs and potential moderators of change in body fat percentage, whole-body fat and lean mass, muscle hypertrophy, muscle strength, and muscle power/rapid force in healthy young women (between 18 and 35 years). A systematic search was undertaken in 7 databases from inception to May 2022. Eligible randomized controlled trials examined the effects of resistance-based exercise programs on outcomes of interest in healthy young women. Meta-analysis was undertaken with a 3-level mixed-effects model. Associations between standardized mean difference (SMD) and potential moderators (number of sessions, weekly volume, and intensity) were tested by meta-regression models. Statistical significance was set at an a level of 0.05, whereas an a level of 0.05-0.10 was also considered for potential moderators of resistance training effects. Forty articles (n = 1,312) were included. Resistance-based exercise programs resulted in a significant improvement of 0.4 SMD (95% confidence intervals [95% CI]: 0.2 to 0.5, p < 0.001) in lean mass/muscle hypertrophy and 1.2 SMD (95% CI: 0.9 to 1.5, p < 0.001) in muscle strength. A higher number of sessions was associated with changes in lean mass/muscle hypertrophy (β = 0.01 ± 0.00, p = 0.009), whereas a higher weekly volume approached statistical significance to moderate changes in muscle strength (β = 0.01 ± 0.01, p = 0.053). Body fat percentage (-0.4 SMD, 95% CI: -0.6 to -0.1, p = 0.006) and muscle power/rapid force (0.6 SMD, 95% CI: 0.2 to 1.1, p = 0.011) were significantly improved. In conclusion, a higher resistance training volume was associated with greater improvements in lean mass/muscle hypertrophy, muscle strength, and body fat percentage, whereas muscle power/rapid force improvements were observed irrespective of prescription characteristics. These findings may help in designing resistance training programs for muscle hypertrophy, strength and power, and body fat percentage in healthy women. [ABSTRACT FROM AUTHOR]

Different methods can be used to assess muscle hypertrophy, but the effects of training on regional changes in muscle size can be detected only using direct muscle measurements such as muscle thickness, cross-sectional area, or volume. Importantly, muscle size increases vary across regions within and between muscles after resistance training programs (i.e., heterogeneous, or nonuniform, muscle hypertrophy). Muscle architectural changes, including fascicle length and pennation angle, after resistance and stretch training programs are also region-specific. In this paper, we show that the literature indicates that a single-site measure of muscle shape does not properly capture the effects achieved after exercise training interventions and that conclusions concerning the magnitude of muscle adaptations can vary substantially depending on the muscle site to be examined. Thus, we propose that measurements of muscle size and architecture should be completed at multiple sites across regions between the agonist muscles within a muscle group and along the length of the muscles to provide an adequate picture of training effects. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effect of progressively adding sets for the lower limb every 2 wk versus performing a constant set volume in resistance-trained males. Methods: Thirty-one resistance-trained males (age = 24.4 ± 2.9 yr, height = 175.5 ± 6.5 cm, body mass = 80.1 ± 9.4 kg, body fat = 14.4% ± 3.1%, resistance training [RT] experience = 5.1 ± 2.2 yr; one-repetition maximum [1RM] barbell back squat: body mass ratio = 1.7 ± 0.1 a.u.) were randomly allocated into a constant group (CG, n = 10), a four-set progression group (4SG, n = 10) or a six-set progression group (6SG, n = 11). After a 2-wk washout period and another 2-wk familiarization period, participants performed a lower-limb training program twice a week for 12 wk. Maximum dynamic strength (1RM) in the barbell back squat, vastus lateralis cross-sectional area, and the sum of lateral thigh muscle thickness at 30%, 50%, and 70% of the femur length were assessed at baseline and after the 12-wk training program. Results: Regarding 1RM, multiple comparisons revealed that 6SG elicited higher muscle strength gains than 4SG (P = 0.002) and CG (P < 0.0001), and 4SG had greater improvements than CG (P = 0.023). Cross-sectional area and sum of lateral thigh muscle thickness showed no between-group differences (P = 0.067 and P = 0.076, respectively). However, an inspection of 95% confidence intervals suggests a potential dose–response relationship, with results appearing to plateau in the higher volume conditions. Conclusions: Our results suggest that progressively adding four or six sets per week every 2 wk elicited greater lower-limb strength in resistance-trained individuals over a 12-wk training period. Although our findings indicate a possible small benefit for higher volume conditions regarding hypertrophic adaptations in this population, the limited certainty of our findings warrants caution. [ABSTRACT FROM AUTHOR]

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor–deficient mice and high-fat diet/streptozotocin–induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid–incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin–induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell–derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator–activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

This article discusses a case of a 16-year-old boy with left ventricular hypertrophy (LVH) and preexcitation on an electrocardiogram (ECG). The boy presented with symptoms of shortness of breath and swelling of the feet, and further examination revealed LVH and severe impairment of the left ventricular ejection fraction. The presence of preexcitation in a background of LVH may indicate underlying conditions such as Danon disease, PRKAG2 mutation cardiomyopathy, Fabry disease, Pompe disease, or mitochondrial disorders. In this case, the patient was diagnosed with Danon disease, a rare X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and intellectual disability. The article emphasizes the importance of careful interpretation of ECG findings and the need for clinical correlation and genetic testing to determine the underlying cause of heart failure. [Extracted from the article]

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLUPP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002–1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03–1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomererelated P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%–63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%–40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosinbinding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM. [ABSTRACT FROM AUTHOR]

BACKGROUND: Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. METHODS: This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. RESULTS: A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63682 athlete-years (95% CI, 1:54065–1:75010). Incidence was higher in male athletes than in female athletes (1:43348 [95% CI, 1:36228–1:51867] versus 1:164504 [95% CI, 1:110552–1:244787] athlete-years, respectively) and Black athletes compared with White athletes (1:26704 [1:20417–1:34925] versus 1:74581 [1:60247–1:92326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61–0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94–1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). CONCLUSIONS: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effects of low-load blood flow restriction (BFR) training on shoulder muscle thickness, rotator cuff (RC) strength, and shoulder symptoms in patients with RC tendinopathy. Design: A randomized, assessor-blinded, controlled trial. Settings: Physiotherapy clinic at a university. Participants: Twenty-eight patients were randomized into an 8-week (2 times/week) shoulder rehabilitation, that is, BFR or non-BFR group. Interventions: BFR training. Main outcome measures: (1) RC, deltoid, scapula retractor, and biceps muscle thicknesses and shoulder internal rotation (IR) and external rotation (ER) strengths. (2) Shoulder pain/function. Results: The BFR group had a greater increase in biceps muscle thickness (P 5 0.002) and shoulder IR strength at 60 degrees/s (P 5 0.040) than the non-BFR group. No differences between the 2 groups were observed in other measurements. Significant improvements in supraspinatus, infraspinatus, and scapula retractor muscle thicknesses and in shoulder ER and IR strengths were observed over time in both the groups (all P, 0 .05). Also, shoulder pain decreased and shoulder function increased over time in both the groups (all P, 0 .05). Conclusions: Low-load BFR training resulted in a greater increase in biceps thickness and shoulder IR strength compared with the non-BFR group in patients with RC tendinopathy. However, there was no superiority of either exercise training regarding the RC, scapula retractor, deltoid muscle thicknesses, or improvements in shoulder ER strength and shoulder pain/function. Clinical Trial Registry Name and Registration Number: The study was registered in ClinicalTrials.gov named Blood Flow Restriction Training in Patients with Shoulder Pain and the registration number is NCT04333784. [ABSTRACT FROM AUTHOR]

The article describes the case of a 65-year old male patient with a medical history of COPD, hypertension, type 2 diabetes mellitus and stage 3A chronic kidney disease and was diagnosed with rectus sheath hematoma (RSH). The patient demonstrated cardiomegaly, progressive abdominal pain, ecchymosis, abdominal distension and metabolic acidosis. The clinical presentation and classification of RSH, complications, common signs and symptoms, and treatment are discussed.

It is unclear whether human tendon adapts to moderate-intensity, high-volume long-term eccentric exercise, e.g., downhill running (DR) training. This study aimed to investigate the time course of patellar tendon (PT) adaptation to short-term DR training and to determine whether changes in PT properties were related to changes in mechanical stress or loading history. Twelve untrained, young, healthy adults (5 women and 7 men) took part in 4 weeks' DR training, comprising 10 sessions. Running speed was equivalent to 60-65% VÌO2max, and session duration increased gradually (15-30 minutes) throughout training. Isometric knee extensor maximal voluntary torque (MVT), vastus lateralis (VL) muscle physiological cross-sectional area (PCSA) and volume, and PT CSA, stiffness, and Young's modulus were assessed at weeks 0, 2, and 4 using ultrasound and isokinetic dynamometry. Patellar tendon stiffness (+6.4 ± 7.4%), Young's modulus (+6.9 ± 8.8%), isometric MVT (+7.5 ± 12.3%), VL volume (+6.6 ± 3.2%), and PCSA (+3.8 ± 3.3%) increased after 4 weeks' DR (p < 0.05), with no change in PT CSA. Changes in VL PCSA correlated with changes in PT stiffness (r = 0.70; p = 0.02) and Young's modulus (r = 0.63; p = 0.04) from 0 to 4 weeks, whereas changes in MVT did not correlate with changes in PT stiffness and Young's modulus at any time point (p > 0.05). To conclude, 4 weeks' DR training promoted substantial changes in PT stiffness and Young's modulus that are typically observed after high-intensity, low-volume resistance training. These tendon adaptations seemed to be driven primarily by loading history (represented by VL muscle hypertrophy), whereas increased mechanical stress throughout the training period did not seem to contribute to changes in PT stiffness or Young's modulus. [ABSTRACT FROM AUTHOR]

BACKGROUND: Microvasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy. METHODS: We used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes Mybpc3 (cardiac myosin binding protein C3) or Myh6 (myosin heavy chain 6). We performed complementary molecular methods to assess protein quantity, interactions, and post-translational modifications to identify mechanisms regulating this response. We manipulated select molecular pathways in vivo using both genetic and pharmacological methods to validate these mechanisms. RESULTS: We found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models. CONCLUSIONS: Our results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the effects of free-weight andmachine-based resistance training on strength, hypertrophy, and joint discomfort. Methods: Thirty-eight resistance-trained men participated in an 8-wk resistance program allocated into free-weight (n = 19) or machine-based (n = 19) groups. Training variables were identical for both modalities, so they only differed in the use of barbells or machines to execute the full squat, bench press, prone bench pull, and shoulder press exercises. The velocity-based method was implemented to accurately adjust the intensity throughout the program. Strength changes were evaluated using eight velocity-monitored loading tests (four exercises two modalities) and included the relative one-repetition maximum (1RMRel), as well as the mean propulsive velocity against low (MPVLow) and high (MPVHigh) loads. Ultrasound-derived cross-sectional area of quadriceps (proximal and distal regions), pectoralis major, and rectus abdominis was measured to examine hypertrophy. Complementarily, Western Ontario and McMaster Universities and Disabilities of the Arm, Shoulder and Hand questionnaires were administrated to assess changes in lower- and upper-limb joint discomfort. Outcomes were compared using ANCOVA and percentage of change (Δ) statistics. Results: Each group significantly ( P < 0.001) increased 1RMRel, MPVLow, and MPVHigh for both modalities tested, but especially in the one they trained.When considering together the eight exercises tested, strength changes for both modalities were similar (Δ differences ≤1.8%, P ≥ 0.216). Likewise, the cross-sectional area of all the muscles evaluated was significantly increased by both modalities, with no significant differences between them (Δ difference ≤2.0%, P ≥ 0.208). No between-group differences ( P ≥ 0.144) were found for changes in stiffness, pain, and functional disability levels, which were reduced by both modalities. Conclusions: Free-weight and machine-based modalities are similarly effective to promote strength and hypertrophy without increasing joint discomfort. [ABSTRACT FROM AUTHOR]

BACKGROUND: Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus. METHODS: We subjected cardiac-specific Snrk-/- mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR. RESULTS: Cardiac-specific Snrk-/- mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro Snrk knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells. CONCLUSIONS: These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology. [ABSTRACT FROM AUTHOR]

Study Design. Retrospective cohort study. Objective. To clarify whether outcomes of anterior cervical discectomy and fusion (ACDF) differ according to the presence of posterior cord compression from the ligamentum flavum (CCLF) Summary of Background Data. Although ACDF effectively addresses anterior cord compression from disc material and bone spurs, it cannot address posterior compression. Whether ACDF could result in favorable outcomes when CCLF is present remains unclear. Patients and Methods. A total of 195 consecutive patients who underwent ACDF and were followed up for >2 years were included. CCLF was graded based on magnetic resonance imaging findings. Patients with CCLF grade 2 were classified as such, whereas patients with CCLF grades 0 to 1 were classified as the no- CCLF group. Patient characteristics, cervical sagittal parameters, neck pain visual analog scale, arm pain visual analog scale, and Japanese Orthopedic Association (JOA) score were assessed. Categorical variables were analyzed using a χ² test, whereas continuous variables were analyzed using the Student t test. Multivariable logistic regression analysis was performed to elucidate factors associated with JOA recovery rates of > 50%. Results. One hundred sixty-seven patients (85.6%) were included in the no-CCLF group, whereas the remaining 28 patients (14.4%) were included in the CCLF group. Among patients in the CCLF group, 14 patients (50.0%) achieved clinical improvement. JOA score significantly improved in the no-CCLF group after the operation (P < 0.001), whereas improvement was not appreciated in the CCLF group (P = 0.642). JOA scores at 3 months (P = 0.037) and 2 years (P = 0.001) postoperatively were significantly higher in the no-CCLF group. Furthermore, the JOA recovery rate at 2 years after surgery was significantly higher in the no-CCLF group (P = 0.042). Logistic regression demonstrated that CCLF was significantly associated with a JOA recovery rate of >50% at 2 years after surgery (odds ratio: 2.719; 95% CI: 1.12, 6.60). Conclusion. ACDF performed for patients with CCLF grade 2 showed inferior JOA score improvement compared with those with CCLF grade 0 or 1. ACDF cannot remove posterior compressive structures, which limits its utility when ligamentum flavum significantly contributes to cord compression. [ABSTRACT FROM AUTHOR]

Study Design. Histologic analysis of the ligamentum flavum (LF) in the lumbar spine. Objective. The objective of this study is to investigate the levels of glycogen synthase kinase-3β (GSK-3β) and β-catenin in the LF tissue of patients with lumbar spinal stenosis (LSS). Summary of Background Data. The hypertrophy of the LF is the primary cause of the progression of LSS. Recently, Wnt signaling has been proposed as one of the molecular processes contributing to LF hypertrophy. GSK-3β and β-catenin are recognized to play a crucial part in the control of this signaling pathway. Materials and Methods. From May 2020 to July 2022, LF from 51 LSS patients (LSS group) and 18 lumbar disc herniation patients (control group) were prospectively collected during surgery. Histologic analysis was investigated to confirm the progression of LF fibrosis. The levels of α-smooth muscle actin, phosphorylation of GSK-3β (p-GSK-3β; inactive form), and β-catenin were analyzed in LF withWestern blot analysis to reveal the GSK-3β/β-catenin signaling pathway. Continuous variables are expressed as mean±SD and compared using the student t test. Categorical variables are compared using the χ² test or Fisher exact test, as appropriate. To determine the association between p-GSK-3β and LF thickness, the Pearson correlation coefficient was calculated based on the results of Western blot analysis. Results. The LSS group was older and had thicker LF than the controls. The LSS group showed increased collagen fiber and cellularity than the controls. The levels of α-smooth muscle actin, p-GSK-3β, and β-catenin in the LF of the LSS group were significantly higher than that of the control group. There was a strong positive correlation between p-GSK-3β (Ser9) level and LF thickness in LSS patients (r=0.69, P= 0.01). Conclusion. This research proposes a molecular mechanism for the pathogenesis of LF hypertrophy in LSS. Specifically, GSK-3β/β-catenin signaling appears to be related to LF hypertrophy in LSS and a positive correlation exists between p-GSK-3β level and LF thickness. [ABSTRACT FROM AUTHOR]

BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2--wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2--wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF. [ABSTRACT FROM AUTHOR]

This study investigated the effects of low-intensity torque-matched isometric training on muscle hypertrophy and strengthening at long (LL) and short muscle lengths (SL). Twentyeight young subjects completed an 8-week hamstring isometric training program (30% of maximal voluntary contraction (MVC)35 s x 20 repetitions x 5 sets x 3 times/week) at 30° knee flexion (LL) or 90° knee flexion (SL). The cross-sectional area (CSA) of the hamstrings and MVC were measured before and after the intervention. The active torque because of muscle contraction was calculated by subtracting the passive torque at rest from the total torque (30% MVC). The active torque was significantly lower in the LL training group than in the SL training group (p < 0.01), whereas there was no between-group difference in total torque during training. For CSA and MVC at 30° knee flexion, the split-plot analysis of variance (ANOVA) showed no significant time 3 group interaction; however, it did show a significant main effect of time (p < 0.05), indicating a significant increase after training intervention. As for MVC at 90° knee flexion, there was a significant time3group interaction (p < 0.05) and a significant simple main effect of time in both the LL (p < 0.01; Cohen's d effect size [ES] = 0.36) and SL (p < 0.01; ES = 0.64) training groups. Therefore, low-intensity isometric training at LL can induce hypertrophy and strengthening, even in cases where the active torque production is lower than that at SL, whereas the training at SL may be more effective for muscle strengthening at SL. [ABSTRACT FROM AUTHOR]

Introduction: Athletes use their skeletal muscles to demonstrate performance. Muscle force generating capacity is correlated with volume, meaning that variations in sizes of different muscles may be indicative of how athletes meet different demands in their sports. Medical imaging enables in vivo quantification ofmuscle volumes; however, muscle volume distribution has not been compared across athletes of different sports. Purpose: The goal of this work was to define "muscular phenotypes" in athletes of different sports and compare these using hierarchical clustering. Methods: Muscle volumes normalized by body mass of athletes (football, baseball, basketball, or track) were compared with control participants to quantify size differences using z-scores. z-Scores of 35 muscles described the pattern of volume deviation within each athlete's lower limb, characterizing their muscular phenotype. Data-driven high-dimensional clustering analysis was used to group athletes presenting similar phenotypes. Efficacy of clustering to identify similar phenotypes was demonstrated by grouping athletes' contralateral limbs before other athletes' limbs. Results: Analyses revealed that athletes did not tend to cluster with others competing in the same sport. Basketball players with similar phenotypes grouped by clustering also demonstrated similarities in performance. Clustering also identified muscles with similar volume variation patterns across athletes, and principal component analysis revealed specific muscles that accounted for most of the variance (gluteus maximus, sartorius, semitendinosus, vastus medialis, vastus lateralis, and rectus femoris). Conclusions: Athletes exhibit heterogeneous lower limb muscle volumes that can be characterized and compared as individual muscular phenotypes. Clustering revealed that athletes with the most similar phenotypes do not always play the same sport such that patterns of muscular heterogeneity across a group of athletes reflect factors beyond their specific sports. [ABSTRACT FROM AUTHOR]

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups--overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM--exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G-patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH-compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G-patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy. [ABSTRACT FROM AUTHOR]

Objective: It remains unknown whethermyonuclei remain elevated post anabolic-androgenic steroid (AAS) usage in humans. Limited data exist on AAS-induced changes in gene expression. Design: Cross-sectional/longitudinal. Setting: University. Participants: Fifty-sixmen aged 20 to 42 years. IndependentVariables: Non-resistance-trained (C) or resistance-trained (RT), RT currently using AAS (RT-AS), of which if AAS usage ceased for$18 weeks resampled as Returning Participants (RP) or RT previously using AAS (PREV). MainOutcomeMeasures: Myonuclei per fiber and cross-sectional area (CSA) of trapeziusmuscle fibers. Results: There were no significant differences between C (n 5 5), RT (n 5 15), RT-AS (n 5 17), and PREV (n 5 6) for myonuclei per fiber. Three of 5 returning participants (RP1-3) were biopsied twice. Before visit 1, RP1 ceased AAS usage 34 weeks before, RP2 and RP3 ceased AAS usage#2 weeks before, and all had 28 weeks between visits. Fiber CSA decreased for RP1 and RP2 between visits (7566 vs 6629 mm2; 7854 vs 5677 mm2) while myonuclei per fiber remained similar (3.5 vs 3.4; 2.5 vs 2.6). Respectively, these values increased for RP3 between visits (7167 vs 7889 mm2; 2.6 vs 3.3). Conclusions: This cohort of past AAS users did not have elevated myonuclei per fiber values, unlike previous research, but reported AAS usage was much lower. Training and AAS usage history also varied widely among participants. Comparable myonuclei per fiber numbers despite decrements in fiber CSA postexposure adheres with the musclememory mechanism, but there is variation in usage relative to sampling date and low numbers of returning participants. [ABSTRACT FROM AUTHOR]

Whether there is an optimal range of motion (ROM) to induce muscle hypertrophy remains elusive, especially for gastrocnemius. This study aimed to compare the changes in gastrocnemius muscle thickness between calf raise exercise performed with full ROM (FULLROM), partial ROM performed in the initial (INITIALROM), and final (FINALROM) portions of the ROM. Forty-two young women performed a calf training program for 8 weeks, 3 days⋅week-1, with differences in the calf raise ROM configuration. The calf raise exercise was performed in a pin-loaded, horizontal, leg-press machine, in 3 sets of 15-20 repetition maximum. The subjects were randomly assigned to 1 of the 3 groups: FULLROM (ankle: -25° to +25°), INITIALROM (ankle: -25° to 0°), and FINALROM (ankle: 0°to +25°), where 0° was defined as an angle of 90° of the foot with the tibia. The muscle thickness measurements of medial and lateral gastrocnemius were taken by means of B-mode ultrasound. INITIALROM elicited greater medial gastrocnemius increases than FULLROM and FINALROM (INITIALROM = +15.2% vs. FULLROM = +6.7% and FINALROM = +3.4%; p ≤ 0.009). Furthermore, INITIALROM elicited greater lateral gastrocnemius increases than FINALROM (INITIALROM = +14.9% vs. FINALROM = +6.2%; p < 0.024) but did not significantly differ from FULLROM (FULLROM = +7.3%; p = 0.060). The current results suggest that calf training performed at longer muscle lengths may optimize gastrocnemius muscle hypertrophy in young women. Therefore, when prescribing hypertrophy-oriented training, the inclusion of the calf raise exercise performed with partial ROM in the initial portion of the excursion should be considered. [ABSTRACT FROM AUTHOR]

Editor's note: This is the next installment in a series on electrocardiogram (ECG) interpretation. Nurses in all settings should know the basics, as medications and physiological changes can cause cardiac arrhythmias. Each article will start with a brief case scenario and an ECG strip and then take you step by step through analyzing the heart rhythm. [ABSTRACT FROM AUTHOR]

Purpose: The optimal intensity of resistance training (RT) to improve muscular, physical performance, and metabolic adaptations still needs to be well established for older adults. Based on current position statements, we compared the effects of two different RT loads on muscular strength, functional performance, skeletal muscle mass, hydration status, and metabolic biomarkers in older women. Methods: One hundred one older women were randomly allocated to perform a 12-wk whole-body RT program (eight exercises, three sets, three nonconsecutive days a week) into two groups: 8-12 repetitions maximum (RM) and 10-15RM. Muscular strength (1RM tests), physical performance (motor tests), skeletal muscle mass (dual-energy X-ray absorptiometry), hydration status (bioelectrical impedance), and metabolic biomarkers (glucose, total cholesterol, HDL-c, HDL-c, triglycerides, and C-reactive protein) were measured at baseline and posttraining. Results: Regarding muscular strength, 8-12RM promoted higher 1RM increases in chest press (+23.2% vs +10.7%, P < 0.01) and preacher curl (+15.7% vs +7.4%, P < 0.01), but not in leg extension (+14.9% vs +12.3%, P > 0.05). Both groups improved functional performance (P <0.05) in gait speed (4.6%-5.6%), 30 s chair stand (4.6%-5.9%), and 6 min walking (6.7%-7.0%) tests, with no between-group differences (P > 0.05). The 10-15RM group elicited superior improves in the hydration status (total body water, intracellular and extracellular water; P < 0.01), and higher gains of skeletal muscle mass (2.5% vs 6.3%, P < 0.01), upper (3.9% vs 9.0%, P < 0.01) and lower limbs lean soft tissue (2.1% vs 5.4%, P < 0.01). Both groups improved their metabolic profile. However, 10-15RM elicited greater glucose reductions (-0.2% vs -4.9%, P < 0.05) and greater HDL-c increases (-0.2% vs +4.7%, P < 0.01), with no between-group differences for the other metabolic bio-markers (P > 0.05). Conclusions: Our results suggest that 8-2RM seems more effective than 10-15RM for increasing upper limbs' muscular strength, whereas the adaptative responses for lower limbs and functional performance appear similar in older women. In contrast, 10-15RM seems more effective for skeletal muscle mass gains, and increased intracellular hydration and improvements in metabolic profile may accompany this adaptation. [ABSTRACT FROM AUTHOR]

Background: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. Methods: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. Results: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. Conclusions: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well. [ABSTRACT FROM AUTHOR]

Resistance exercise range of motion (ROM) influences muscular adaptations. However, there are no consistent practical guidelines about the optimal ROM for maximizing muscle hypertrophy. The objective of this article was to systematically review the literature for studies that compared the effects of full ROM (fROM) and partial ROM (pROM) on muscle hypertrophy. PubMed/MEDLINE, Scopus, and Web of Science databases were searched to identify articles from the earliest record up to and including April 2022. We calculated the effect size (ES) scores of the variables of interest. Eleven studies were included in the review. Full ROM and pROM performed in the initial part of the ROM elicited greater muscle hypertrophy of the rectus femoris, vastus lateralis, biceps brachii, and brachialis distal sites (between-groups ES: 0.20–0.90) than pROM performed in the final part of the ROM. fROM elicited greater muscle growth on the gluteus maximus and adductors than pROM in the final part of the ROM (between-groups ES: 0.24–0.25). Initial pROM produced more favorable proximal rectus femoris hypertrophy than fROM (between-groups ES: 0.35–0.38). pROM in the middle part of the ROM elicited greater triceps brachii hypertrophy than fROM (between-group ES: 1.21). In conclusion, evidence suggests that when training at a longer muscle length—through either pROM or fROM—some muscles, such as quadriceps femoris, biceps brachii, and triceps brachii, tend to experience optimal growth. Thus, the use pROM in the initial part of the excursion in combination with fROM training should be considered when prescribing hypertrophy-oriented resistance training programs. [ABSTRACT FROM AUTHOR]

This project examined the differences between a single set (SS) compared to multiple sets (MS) of resistance exercise on the Akt/protein kinase B (PKB) signaling pathway, the expression of insulin-like growth factor-1 (IGF-1), and the receptor for IGF-1 (IGF-1R) to better understand the types of resistance training protocols that are most beneficial in stimulating the muscle hypertrophic response. Sixteen healthy men were randomly selected into 2 groups of 8. Subjects in each group received 3 biopsies: (a) before exercise, (b) 15 minutes postexercise, and (c) 180 minutes postexercise. Subjects in the SS group performed 1 set of leg press to failure at 80% of their predetermined 1 repetition maximum (1RM). Subjects in the MS group performed 2 sets of 10 repetitions and 1 set to failure at 80% of their predetermined 1RM, with 3 minutes of rest between each set. Our results indicated no group 3 time interactions in the concentration of Akt signaling proteins. Furthermore, there were no group 3 time interactions in IGF-1 or IGF-1R expression. However, phosphorylated 4E-binding protein 1 levels increased 150% from pre to 180 minutes post (p = 0.005). In addition, there was a significantly greater increase in IGF-1R expression in the SS group compared with the MS group (7.99±10.07 vs. 4.41 ± 6.28; p = 0.026). Collectively, we found that a SS of resistance training evokes a similar acute Akt/PKB pathway response as MS in recreationally active men. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare and rank gluteal muscle forces in eight hip-focused exercises performed with and without external resistance and describe the underlying fiber lengths, velocities, and muscle activations. Methods: Motion capture, ground reaction forces, and electromyography (EMG) were used as input to an EMG-informed neuromusculoskeletal model to estimate gluteus maximus, medius, and minimus muscle forces. Participants were 14 female footballers (18–32 yr old) with at least 3 months of lower limb strength training experience. Each participant performed eight hip-focused exercises (single-leg squat, split squat, single-leg Romanian deadlift [RDL], single-leg hip thrust, banded side step, hip hike, side plank, and side-lying leg raise) with and without 12 repetition maximum (RM) resistance. For each muscle, exercises were ranked by peak muscle force, and k-means clustering separated exercises into four tiers. Results: The tier 1 exercises for gluteus maximus were loaded split squat (95% confidence interval [CI] = 495–688 N), loaded single-leg RDL (95% CI = 500–655 N), and loaded single-leg hip thrust (95% CI = 505–640 N). The tier 1 exercises for gluteus medius were body weight side plank (95% CI = 338–483 N), loaded single-leg squat (95% CI = 278–422 N), and loaded single-leg RDL (95% CI = 283–405 N). The tier 1 exercises for gluteus minimus were loaded single-leg RDL (95% CI = 267–389 N) and body weight side plank (95% CI = 272–382 N). Peak gluteal muscle forces increased by 28–150 N when exercises were performed with 12RM external resistance compared with body weight only. Peak muscle force coincided with maximum fiber length for most exercises. Conclusions: Gluteal muscle forces were exercise specific, and peak muscle forces increased by varying amounts when adding a 12RM external resistance. These findings may inform exercise selection by facilitating the targeting of individual gluteal muscles and optimization of mechanical loads to match performance, injury prevention, or rehabilitation training goals. [ABSTRACT FROM AUTHOR]

Study Design.: We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL). Objective.: To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL. Summary of Background Data.: Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear. Methods.: Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors. Results.: Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9 , Runx2 , and SIRT1. In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front. Conclusions.: IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL. [ABSTRACT FROM AUTHOR]

The purpose of this systematic review with meta-analysis was to explore the effects of concurrent resistance and endurance training (CT) incorporating continuous or intermittent endurance training (ET) on whole-muscle and type I and II muscle fiber hypertrophy compared with resistance training (RT) alone. Randomized and nonrandomized studies reporting changes in cross-sectional area at muscle fiber and whole-muscle levels after RT compared with CT were included. Searches for such studies were performed in Web of Science, PubMed, Scopus, SPORTDiscus, and CINAHL electronic databases. The data reported in the included studies were pooled in a random-effects meta-analysis of standardized mean differences (SMDs). Twenty-five studies were included. At the whole-muscle level, there were no significant differences for any comparison (SMD < 0.03). By contrast, RT induced greater type I and type II muscle fiber hypertrophy than CT when high-intensity interval training (HIIT) was incorporated alone (SMD > 0.33) or combined with continuous ET (SMD > 0.27), but not compared with CT incorporating only continuous ET (SMD < 0.16). The subgroup analyses of this systematic review and meta-analysis showed that RT induces greater muscle fiber hypertrophy than CT when HIIT is included. However, no CT affected whole-muscle hypertrophy compared with RT. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to compare the effects of 2 different periodized resistance training programs on maximal strength, power, and muscle architecture, in trained individuals. Twenty-two resistance-trained men were randomly assigned to either a mixed session training group (MSP; n = 11; age = 23.7 ± 2.6 years; body mass = 80.5 ± 9.8 kg; height = 175.5 ± 6.1 cm) or a block periodization group (BP; n = 11; age = 25.7 ± 4.6 years; body mass = 81.1 ± 10.7 kg; height = 176.8 ± 8.4 cm). Both training programs were 10 weeks in duration and were equated in volume. Each training session of the MSP focused on power, maximal strength, and hypertrophy, whereas each mesocycle within the BP focused on one of these components. Subjects were assessed for body composition, muscle architecture, maximal strength, and power. In addition, perceived training load, and training volume were calculated. Subjects in MSP experienced greater improvements in fat free mass (p = 0.021), muscle thickness of the pectoralis and vastus lateralis (p < 0.05), and a greater improvement in 1RM bench press (p < 0.001; +8.6% in MSP and +2% in BP) than in BP. By contrast, BP resulted in greater improvements in vertical jump (p = 0.022; +7.2%) compared with MSP (+1.2%). No significant differences were noted between the groups for perceived training load (p = 0.362) nor training volume (p = 0.169). Results of this study indicated that in a 10-week training study, MSP may enhance muscle hypertrophy and maximal strength to a greater extent than BP, with the same training volume and perceived training load. However, BP may be more effective for vertical jump improvement. [ABSTRACT FROM AUTHOR]

Purpose: Sprinters exhibit inhomogeneous muscularity corresponding to musculoskeletal demand for sprinting execution. An inhomogeneous morphology would affect the mass distribution, which in turn may affect the mechanical difficulty in moving from an inertia perspective; however, the morphological characteristics of sprinters from the inertia perspective have not been examined. Here we show no corresponding differences in the normalized mass and normalized moment of inertia between the sprinters and untrained nonsprinters. Methods: We analyzed fat- and water-separated magnetic resonance images from the lower limbs of 11 male sprinters (100 m best time of 10.44–10.83 s) and 12 untrained nonsprinters. We calculated the inertial properties by identifying the tissue of each voxel and combining the literature values for each tissue density. Results: The lower-limb relative mass was significantly larger in sprinters (18.7% ± 0.7% body mass) than in nonsprinters (17.6% ± 0.6% body mass), whereas the normalized moment of inertia of the lower limb around the hip in the anatomical position was not significantly different (0.044 ± 0.002 vs 0.042 ± 0.002 [a. u.]). The thigh relative mass in sprinters (12.9% ± 0.4% body mass) was significantly larger than that in nonsprinters (11.9% ± 0.4% body mass), whereas the shank and foot relative masses were not significantly different. Conclusions: We revealed that the mechanical difficulty in swinging the lower limb is not relatively larger in sprinters in terms of inertia, even though the lower-limb mass is larger, reflecting their muscularity. We provide practical implications that sprinters can train without paying close attention to the increase in lower-limb mass and moment of inertia. [ABSTRACT FROM AUTHOR]

Purpose: Resistance exercise training (RET) attenuates age-related muscle and strength loss ("sarcopenia"). However, compared with machine-based RET, the efficacy of cost-effective, accessible elastic band RET (EB-RET) for muscle adaptive remodeling lacks supporting mechanistic evidence. Methods: Eight young (YM; 24 ± 4 yr) and eight older (OM; 68 ± 6 yr) untrained males consumed an oral stable isotope tracer (D2O) combined with serial vastus lateralis muscle biopsies to measure integrated myofibrillar protein synthesis (iMyoPS) and regulatory signaling over ~48 h before (habitual) and after an acute bout of EB-RET (6 × 12 repetitions at ~70% of one-repetition maximum). iMyoPS was determined via gas chromatography–pyrolysis–isotope ratio mass spectroscopy and regulatory signaling expression by immunoblot. Results: Habitual iMyoPS did not differ between YM and OM (1.62% ± 0.21% vs 1.43% ± 0.47%·d−1, respectively, P = 0.128). There was a significant increase in iMyoPS after EB-RET in YM (2.23% ± 0.69%·d−1, P = 0.02), but not OM (1.75% ± 0.54%·d−1, P = 0.30). EB-RET increased the phosphorylation of key anabolic signaling proteins similarly in YM and OM at 1 h postexercise, including p-IRS-1Ser636/639, p-AktSer473, p-4EBP-1Thr37/46, p-P70S6KThr389, and p-RPS6Ser240/244, whereas p-TSC2Thr1462 and p-mTORSer2448 increased only in YM (all P < 0.05). There were no differences in the expression of amino acid transporters/sensors or proteolytic markers after EB-RET. Conclusions: iMyoPS was elevated after EB-RET in YM but not OM. However, the increase in acute anabolic signaling with EB-RET was largely similar between groups. In conclusion, the capacity for EB-RET to stimulate iMyoPS may be impaired in older age. Further work may be necessary to optimize prescriptive programming in YM and OM. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy. Methods: We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene Il1rl1 (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type–specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well. Results: Mice deficient in Il33 were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, but not in mice lacking Il1rl1. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte–specific deletion of Il1rl1 but not in endothelial cell- or fibroblast-specific deletion of Il1rl1. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy. Conclusions: These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease. [ABSTRACT FROM AUTHOR]

Background: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that NLRP3 (neural signals activate the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart.Methods: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed.Results: Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload.Conclusions: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease. [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein–interacting membrane protein (VIMP), positing that VIMP would be adaptive in pathological cardiac hypertrophy in mice. Methods: We developed a new method involving cardiac myocyte-specific adeno-associated virus serovar 9–mediated expression of the canonical ERAD substrate, TCRα, to measure the rate of ERAD, ie, ERAD flux, in the heart in vivo. Adeno-associated virus serovar 9 was also used to either knock down or overexpress VIMP in the heart. Then mice were subjected to transverse aortic constriction to induce pressure overload–induced cardiac hypertrophy. Results: ERAD flux was slowed in both human heart failure and mice after transverse aortic constriction. Surprisingly, although VIMP adaptively contributes to ERAD in model cell lines, in the heart, VIMP knockdown increased ERAD and ameliorated transverse aortic constriction–induced cardiac hypertrophy. Coordinately, VIMP overexpression exacerbated cardiac hypertrophy, which was dependent on VIMP engaging in ERAD. Mechanistically, we found that the cytosolic protein kinase SGK1 (serum/glucocorticoid regulated kinase 1) is a major driver of pathological cardiac hypertrophy in mice subjected to transverse aortic constriction, and that VIMP knockdown decreased the levels of SGK1, which subsequently decreased cardiac pathology. We went on to show that although it is not an ER protein, and resides outside of the ER, SGK1 is degraded by ERAD in a noncanonical process we call ERAD-Out. Despite never having been in the ER, SGK1 is recognized as an ERAD substrate by the ERAD component DERLIN1, and uniquely in cardiac myocytes, VIMP displaces DERLIN1 from initiating ERAD, which decreased SGK1 degradation and promoted cardiac hypertrophy. Conclusions: ERAD-Out is a new preferentially favored noncanonical form of ERAD that mediates the degradation of SGK1 in cardiac myocytes, and in so doing is therefore an important determinant of how the heart responds to pathological stimuli, such as pressure overload. [ABSTRACT FROM AUTHOR]

This exploratory secondary data analysis compared the effects of a percentage of 1 repetition maximum (%1RM) and a repetition zone (RM Zone) progression model carried out to muscle failure on volume load progression (VLPro), muscle strength, and cross-sectional area (CSA). The sample comprised 24 untrained men separated in 2 groups: %1RM (n = 14) and RM Zone (n = 10). Muscle CSA and muscle strength (1RM) were assessed before and after 24 training sessions, and an analysis of covariance was used. Volume load progression and accumulated VL (VLAccu) were compared between groups. The relationships between VLProg, VLAccu, 1RM, and CSA increases were also investigated. A significance level of p = 0.05 was adopted for all statistical procedures. Volume load progression was greater for RM Zone compared with %1RM (2.30 ± 0.58% per session vs. 1.01 ± 0.55% per session; p < 0.05). Significant relationships were found between 1RM and VLProg (p < 0.05) and CSA and VLProg (p < 0.05). No between-group differences were found for VLAccu (p > 0.05). Analysis of covariance revealed no between-group differences for 1RM absolute (p < 0.05) or relative changes (p < 0.05). However, post hoc testing revealed greater absolute and relative changes in CSA for the RM Zone group compared with the %1RM group (p < 0.001). In conclusion, RM Zone resulted in a greater VLPro rate and muscle CSA gains compared with %1RM, with no differences in VLAccu and muscle strength gains between progression models. [ABSTRACT FROM AUTHOR]

It is anticipated that flywheel-based leg resistance exercise will be implemented in future long-duration space missions, to counter deconditioning of weight-bearing bones and postural muscles. The aim was to examine low back loads and muscle engagements during flywheel leg press (FWLP) and flywheel squat (FWS) and, for comparisons, free-weight barbell back squat (BBS). Eight resistance-trained subjects performed 8 repetition maximums of FWLP, FWS, and BBS. Motion analysis and inverse dynamics-based musculoskeletal modeling were used to compute joint loads and muscle forces. Muscle activities were measured with electromyography (EMG). At the L4-L5 level, peak vertebral compression force was similarly high in all exercise modes, whereas peak vertebral posteroanterior shear force was greater (p < 0.05) in FWLP and BBS than in FWS. Among the back-extensor muscles, the erector spinae longissimus exerted the greatest peak force, with no difference between exercises. Peak force in the lumbar multifidus was lower (p < 0.05) during FWLP than during FWS and BBS. Peak EMG activity in the lumbar extensor muscles ranged between 31 and 122% of maximal voluntary isometric contraction across muscles and exercise modes, with the greatest levels in the lumbar multifidus. The vertebral compression forces and muscle activations during the flywheel exercises were sufficiently high to presume that when implementing such exercise in space countermeasure regimens, they may be capable of preventing muscle atrophy and vertebral demineralization in the lumbar region. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear.Methods: VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure.Results: We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH.Conclusions: Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase 3A (PDE3A) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective.Methods: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca2+ imaging. We used Förster resonance energy transfer and biochemical assays.Results: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding.Conclusions: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage. [ABSTRACT FROM AUTHOR]

Keywords: Editorials; AKAP; cardiac hypertrophy; cyclic AMP; cell signaling; hypertension; phosphodiesterase; subcellular compartmentalization EN Editorials AKAP cardiac hypertrophy cyclic AMP cell signaling hypertension phosphodiesterase subcellular compartmentalization 1779 1782 4 12/07/22 20221206 NES 221206 Hypertension is a major cause of cardiovascular disease and premature death worldwide. Cardiac hypertrophy, cyclic AMP, cell signaling, hypertension, phosphodiesterase, Editorials, AKAP, subcellular compartmentalization Hypertension with brachydactyly type E is an autosomal dominant disease caused by a gain of function of phosphodiesterase (PDE) 3A, resulting in a decrease of cAMP levels. [Extracted from the article]

Hypertrophic cardiomyopathy (HCM) is a genetic autosomal dominant disorder of the heart muscle that is characterized by left ventricular hypertrophy and sudden cardiac death. It is the most common inherited cardiac disease. HCM is defined by sarcomeric mutations that result in fibrosis of the heart, affecting contraction. In most cases, clinical presentations can range from asymptomatic to systolic and diastolic ventricular dysfunction, arrhythmias, and sudden cardiac death. Some histopathologic features typical of the disease are changes in myocyte disarray and myocardial fibrosis. Mutations in the β-myosin heavy chain and myosin-binding protein C have been identified as the cause of the disease. The goals of pharmacological therapy as well as nonpharmacological therapy are to alleviate the symptoms and to prevent sudden cardiac death. Anatomical defects are treated primarily by surgical intervention, whereas other issues such as hypercontractility are treated with pharmacotherapy. In this article, we review the pathophysiology and treatment options for HCM. [ABSTRACT FROM AUTHOR]

This systematic review examines the effect of dietary nitrate supplementation (SUP) on muscle strength and hypertrophy when combined with physical exercise. The databases PubMed, Web of Science, and MEDLINE were searched for full-text articles published between January 2000 and June 2020. For inclusion, studies had to report on the effects of SUP administered as acute or chronic doses together with a standardized exercise protocol on muscle strength and hypertrophy compared with placebo in healthy adults who were sedentary, physically active, or professional athletes. Twelve studies (1,571 subjects) were finally selected. In 5 studies, the SUP regime was acute, and in 7, it was chronic. SUP was nitrate-rich beetroot juice in 9 studies, a potassium nitrate capsule in 1, and increased dietary nitrate in 2. Ingested nitrate was 64-1,200 mg. Of the 12 studies, 6 observed an ergogenic effect of SUP compared with placebo. These findings indicate that muscle strength gains are possible provided the dose, format, frequency, period, and exercise test are appropriate. Best results were observed with a minimum acute dose of 400 mg of nitrate provided as beetroot juice/shot taken 2-2.5 hours before exercise involving low- and high-intensity muscle contractions. This SUP regime seems to improve muscle efficiency in terms of reduced phosphocreatine and energy costs (P-magnetic resonance spectroscopy) and improved time to exhaustion. [ABSTRACT FROM AUTHOR]

Coratella, G, Beato, M, Bertinato, L, Milanese, C, Venturelli, M, and Schena, F. Including the eccentric phase in resistance training to counteract the effects of detraining in women: a randomized controlled trial. J Strength Cond Res 36(11): 3023–3031, 2022—The current study compared the effects of concentric-based (CONC), eccentric-based (ECC), and traditional concentric-eccentric (TRAD) resistance training on muscle strength, mass, and architecture and the postdetraining retention of the training-induced effects in women. Sixty women were randomly assigned to unilateral volume-equated CONC, ECC, or TRAD knee extension training or control (N = 15 per group). Before training, after an 8-week intervention period, and after an 8-week detraining period, isokinetic concentric, eccentric, and isometric torque were measured. In addition, thigh lean mass was assessed by dual X-ray absorptiometry and vastus lateralis thickness, pennation angle, and fascicle length by ultrasound. After training, concentric and isometric torque increased (p < 0.05) similarly in all groups, whereas eccentric torque increased more in ECC than that in CONC (+13.1%, effect size (ES): 0.71 [0.04–1.38]) and TRAD (+12.6%, ES: 0.60 [0.12–1.08]). Thigh lean mass increased in ECC (+6.1%, ES: 0.47 [0.27–0.67]) and TRAD (+3.1%, ES: 0.33 [0.01–0.65]). Vastus lateralis thickness and pennation angle increased (p < 0.05) similarly in all groups, whereas fascicle elongation was visible in ECC (+9.7%, ES: 0.92 [0.14–1.65]) and TRAD (+7.1%, ES: 0.64 [0.03–1.25]). After detraining, all groups retained (p < 0.05) similar concentric torque. ECC and TRAD preserved eccentric torque (p < 0.05), but ECC more than TRAD (+17.9%, ES: 0.61 [0.21–1.21]). All groups preserved isometric torque (p < 0.05), but ECC more than CONC (+14.2%, ES: 0.71 [0.04–1.38]) and TRAD (+13.8%, ES: 0.65 [0.10–1.20]). Thigh lean mass and vastus lateralis fascicle length were retained only in ECC (p < 0.05), pennation angle was preserved in all groups (p < 0.05), and thickness was retained in CONC and ECC (p < 0.05). Including the eccentric phase in resistance training is essential to preserve adaptations after detraining. [ABSTRACT FROM AUTHOR]

In patients with end-stage nonobstructive HCM and dilated cardiomyopathy at the time of transplant, single nucleus RNA sequencing revealed higher I MME i expression only in fibroblasts, and the degree of I MME i elevation was not significantly different in end-stage nonobstructive HCM versus dilated cardiomyopathy (). Footnotes 1 Nonstandard Abbreviations and Acronyms ARNi angiotensin receptor blocker/neprilysin inhibitor EF ejection fraction HCM hypertrophic cardiomyopathy HF heart failure MME membrane metalloendopeptidase NEP neprilysin oHCM obstructive hypertrophic cardiomyopathy 2 For Sources of Funding and Disclosures, see page 169. Keywords: cardiomyopathy, hypertrophic; heart failure; neprilysin EN cardiomyopathy, hypertrophic heart failure neprilysin 167 169 3 07/07/23 20230711 NES 230711 A frequent narrative is that no medical therapy modifies the natural history of hypertrophic cardiomyopathy (HCM), but evidence shows valsartan and mavacamten modify disease progression in HCM. [Extracted from the article]