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Over the course of the physical activity transition, machines have largely replaced skeletal muscle as the source of work for locomotion and other forms of occupational physical activity in industrial environments. To better characterize this transition and its effect on back muscles and the spine, we tested to what extent typical occupational activities of rural subsistence farmers demand higher magnitudes and increased variability of back muscle activity and spinal loading compared to occupational activities of urban office workers in Rwanda, and whether these differences were associated with back muscle endurance, the dominant risk factor for back pain. Using electromyography, inertial measurement units, and OpenSim musculoskeletal modeling, we measured back muscle activity and spinal loading continuously while participants performed occupational activities for one hour. We measured back muscle endurance using electromyography median frequency analysis. During occupational work, subsistence farmers activate their back muscles and load their spines at 390% higher magnitudes and with 193% greater variability than office workers. Partial correlations accounting for body mass show magnitude and variability response variables are positively associated with back muscle endurance (R = 0.39–0.90 [P < 0.001–0.210] and R = 0.54–0.72 [P = 0.007–0.071], respectively). Body mass is negatively correlated with back muscle endurance (R = -0.60, P = 0.031), suggesting higher back muscle endurance may be also partly attributable to having lower body mass. Because higher back muscle endurance is a major factor that prevents back pain, these results reinforce evidence that under-activating back muscles and under-loading spines at work increases vulnerability to back pain and may be an evolutionary mismatch. As sedentary occupations become more common, there is a need to study the extent to which occupational and leisure time physical activities that increase back muscle endurance helps prevent back pain. [ABSTRACT FROM AUTHOR]

Aim: Patients with osteoporosis who also have sarcopenia are at a high risk for falls and fractures. Early detection of sarcopenia is crucial for these patients. This study aimed to compare the effectiveness of SARC-F, SARC-CalF, and calf circumference (CC) as screening tools for sarcopenia in patients with osteoporosis. Methods: This cross-sectional study was retrospectively conducted on patients who attended the outpatient clinic for Osteoporosis and Sarcopenia at Kyoto Medical Center. Sarcopenia was determined based on low skeletal muscle mass and weak handgrip strength. Sensitivity and specificity analyses were conducted on SARC-F, SARC-CalF, and CC. The diagnostic utility of these three tools was compared using the receiver-operating characteristic (ROC) curves and the area under the ROC curves (AUC). Results: A total of 225 patients (men/women: 33/192) with a median age of 69.0 years (interquartile range: 61.0‒75.0) were enrolled. The prevalence of sarcopenia was found to be 11.6%. CC had the highest sensitivity (80.8%), while SARC-F had the highest specificity (93.0%) for detecting sarcopenia. ROC analysis revealed that all three tools had significant potential for sarcopenia diagnosis, with SARC-CalF having the highest AUC compared to SARC-F and CC (0.753 vs. 0.619 and 0.700). A multivariate logistic regression, incorporating other confounders as explanatory variables, revealed that SARC-CalF was independently related to sarcopenia (odds ratio: 14.80, 95% confidence interval: 3.83–57.30, p < 0.001). Conclusion: In patients with osteoporosis, SARC-CalF is more effective in the early detection of sarcopenia than SARC-F and CC. [ABSTRACT FROM AUTHOR]

Although it is clear that the bioenergetic basis of skeletal muscle fatigue (transient decrease in peak torque or power in response to contraction) involves intramyocellular acidosis (decreased pH) and accumulation of inorganic phosphate (Pi) in response to the increased energy demand of contractions, the effects of old age on the build-up of these metabolites has not been evaluated systematically. The purpose of this study was to compare pH and [Pi] in young (18–45 yr) and older (55+ yr) human skeletal muscle in vivo at the end of standardized contraction protocols. Full study details were prospectively registered on PROSPERO (CRD42022348972). PubMed, Web of Science, and SPORTDiscus databases were systematically searched and returned 12 articles that fit the inclusion criteria for the meta-analysis. Participant characteristics, contraction mode (isometric, dynamic), and final pH and [Pi] were extracted. A random-effects model was used to calculate the mean difference (MD) and 95% confidence interval (CI) for pH and [Pi] across age groups. A subgroup analysis for contraction mode was also performed. Young muscle acidified more than older muscle (MD = -0.12 pH; 95%CI = -0.18,-0.06; p<0.01). There was no overall difference by age in final [Pi] (MD = 2.14 mM; 95%CI = -0.29,4.57; p = 0.08), although sensitivity analysis revealed that removing one study resulted in greater [Pi] in young than older muscle (MD = 3.24 mM; 95%CI = 1.72,4.76; p<0.01). Contraction mode moderated these effects (p = 0.02) such that young muscle acidified (MD = -0.19 pH; 95%CI = -0.27,-0.11; p<0.01) and accumulated Pi (MD = 4.69 mM; 95%CI = 2.79,6.59; p<0.01) more than older muscle during isometric, but not dynamic, contractions. The smaller energetic perturbation in older muscle indicated by these analyses is consistent with its relatively greater use of oxidative energy production. During dynamic contractions, elimination of this greater reliance on oxidative energy production and consequently lower metabolite accumulations in older muscle may be important for understanding task-specific, age-related differences in fatigue. [ABSTRACT FROM AUTHOR]

Circulating blood is an important plasma free amino acids (PFAAs) reservoir and a pivotal link between metabolic pathways. No comparisons are available between athletes with opposite training adaptations that include a broader spectrum of both proteinogenic and non-proteinogenic amino acids, and that take into account skeletal muscle mass. We hypothesized that the levels of the exercise-induced PFAAs concentration are related to the type of training-related metabolic adaptation. We compared highly trained endurance athletes (n = 11) and sprinters (n = 10) aged 20‒35 years who performed incremental exercise until exhaustion. Venous blood was collected before and during the test and 30-min recovery (12 samples). Forty-two PFAAs were assayed using LC-ESI-MS/MS technique. Skeletal muscle mass was estimated using dual X-ray absorptiometry method. Glutamine and alanine were dominant PFAAs throughout the whole exercise and recovery period (~350‒650 μmol∙L-1). Total, combined proteinogenic, non-essential, and non-proteinogenic PFAAs levels were significantly higher in endurance athletes than sprinters (ANOVA group effects: p = 0.007, η2 = 0.321; p = 0.011, η2 = 0.294; p = 0.003, η2 = 0.376; p = 0.001, η2 = 0.471, respectively). The exercise response was more pronounced in endurance athletes, especially for non-proteinogenic PFAAs (ANOVA interaction effect: p = 0.038, η2 = 0.123). Significant between-group differences were observed for 19 of 33 PFAAs detected, including 4 essential, 7 non-essential, and 8 non-proteinogenic ones. We demonstrated that the PFAAs response to incremental aerobic exercise is associated with the type of training-related metabolic adaptation. A greater turnover and availability of circulating PFAAs for skeletal muscles and other body tissues is observed in endurance- than in sprint-trained individuals. Non-proteinogenic PFAAs, despite low concentrations, also respond to exercise loads, indicating their important, though less understood role in exercise metabolism. Our study provides additional insight into the exercise-induced physiological response of PFAAs, and may also provide a rationale in discussions regarding dietary amino acid requirements in high-performance athletes with respect to sports specialization. [ABSTRACT FROM AUTHOR]

Prolonged consumption of diet rich in fats is regarded as the major factor leading to the insulin resistance (IR) and type 2 diabetes (T2D). Emerging evidence link excessive accumulation of bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer), with impairment of insulin signaling in skeletal muscle. Until recently, little has been known about the involvement of long-chain acyl-CoAs synthetases in the above mechanism. To examine possible role of long-chain acyl-coenzyme A synthetase 1 (Acsl1) (a major muscular ACSL isoform) in mediating HFD-induced IR we locally silenced Acsl1 in gastrocnemius of high-fat diet (HFD)-fed C57BL/6J mice through electroporation-delivered shRNA and compared it to non-silenced tissue within the same animal. Acsl1 down-regulation decreased the content of muscular long-chain acyl-CoA (LCACoA) and both the Cer (C18:1-Cer and C24:1-Cer) and DAG (C16:0/18:0-DAG, C16:0/18:2-DAG, C18:0/18:0-DAG) and simultaneously improved insulin sensitivity and glucose uptake as compared with non-silenced tissue. Acsl1 down-regulation decreased expression of mitochondrial β-oxidation enzymes, and the content of both the short-chain acylcarnitine (SCA-Car) and short-chain acyl-CoA (SCACoA) in muscle, pointing towards reduction of mitochondrial FA oxidation. The results indicate, that beneficial effects of Acsl1 partial ablation on muscular insulin sensitivity are connected with inhibition of Cer and DAG accumulation, and outweigh detrimental impact of decreased mitochondrial fatty acids metabolism in skeletal muscle of obese HFD-fed mice. [ABSTRACT FROM AUTHOR]

Plasma levels of branched-chain amino acids and their metabolites, the branched-chain ketoacids are increased in insulin resistance. Our previous studies showed that leucine and its metabolite KIC suppress insulin-stimulated glucose uptake in L6 myotubes along with the activation of the S6K1-IRS-1 pathway. Because other tissue and fiber types can be differentially regulated by KIC, we analyzed the effect of KIC gavage on whole-body insulin sensitivity and insulin signaling in vivo. We hypothesized that KIC gavage would reduce whole-body insulin sensitivity and increase S6K1-IRS-1 phosphorylation in various tissues and muscle fibers. Five-week-old male Sprague-Dawley rats were starved for 24 hours and then gavaged with 0.75ml/100g of water, leucine (22.3g/L) or KIC (30g/L) twice, ten minutes apart. They were then euthanized at different time points post-gavage (0.5-3h), and muscle, liver, and heart tissues were dissected. Other sets of gavaged animals underwent an insulin tolerance test. Phosphorylation (ph) of S6K1 (Thr389), S6 (Ser235/6) and IRS-1 (Ser612) was increased at 30 minutes post leucine gavage in skeletal muscles irrespective of fiber type. Ph-S6 (Ser235/6) was also increased in liver and heart 30 minutes after leucine gavage. KIC gavage increased ph-S6 (Ser235/6) in the liver. Neither Leucine nor KIC influenced whole-body insulin tolerance, nor ph-Akt (Ser473) in skeletal muscle and heart. BCKD-E1 α abundance was highest in the heart and liver, while ph-BCKD-E1 α (Ser293) was higher in the gastrocnemius and EDL compared to the soleus. Our data suggests that only leucine activates the S6K1-IRS-1 signaling axis in skeletal muscle, liver and heart, while KIC only does so in the liver. The effect of leucine and KIC on the S6K1-IRS-1 signaling pathway is uncoupled from whole-body insulin sensitivity. These results suggest that KIC and leucine may not induce insulin resistance, and the contributions of other tissues may regulate whole-body insulin sensitivity in response to leucine/KIC gavage. [ABSTRACT FROM AUTHOR]

Fibrosis is a complex pathological process that can lead to the permanent loss of biological function, with P2ry2 playing a crucial role in this process. Long non-coding RNAs (lncRNAs) have been reported to play an critically important role in the fibrotic process. However, it remains unclear whether lncRNAs can regulate fibrosis through P2ry2. In this study, we detected the expression of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1). We investigated the expression patterns of lnc-MALAT1 and P2ry2 in denervated skeletal muscle, a classical model of fibrosis. Additionally, we utilized a TGF-β-mediated fibrosis model in NIH/3T3 cells to examine the effects of lnc-MALAT1 and P2ry2 on fibroblast activation and the underlying regulatory mechanisms in vitro. Our results demonstrated that the expression levels of lnc-MALAT1 and P2ry2 were consistently elevated in denervated skeletal muscle, correlating with the degree of fibrosis. In vitro experiments confirmed the regulatory effect of lnc-MALAT1 on P2ry2. Furthermore, we identified miR-335-3p as a potential key molecule in the regulatory relationship of lnc-MALAT1/P2ry2. Dual luciferase reporter assays and AGO2-RIP verified the molecular sponging effect of lnc-MALAT1 on miR-335-3p. Additionally, we validated the regulation of the lnc-MALAT1/miR-335-3p/P2ry2 axis through experimental approaches. In conclusion, our study identified a crucial role of lnc-MALAT1/miR-335-3p/P2ry2 axis in fibroblast activation, providing a promising treatment option against the fibrosis. [ABSTRACT FROM AUTHOR]

The endocannabinoid system (ECS) plays a major role in the maintenance of bodily homeostasis and adaptive response to external insults. It has been shown to regulate crucial physiological processes and behaviors, spanning nervous functions, anxiety, cognition, and pain sensation. Due to this broad activity, the ECS has been explored as a potential therapeutic target in the treatment of select diseases. However, until there is a more comprehensive understanding of how ECS activation by exogenous and endogenous ligands manifests across disparate tissues and cells, discretion should be exercised. Previous work has investigated how endogenous cannabinoid signaling impacts skeletal muscle development and differentiation. However, the effects of activation of the ECS by delta-9-tetrahydrocannabinol (THC, the most psychoactive component of cannabis) on skeletal muscle development, particularly in utero, remain unclear. To address this research gap, we used a highly translational non-human primate model to examine the potential impact of chronic prenatal THC exposure on fetal and infant musculoskeletal development. RNA was isolated from the skeletal muscle and analyzed for differential gene expression using a Nanostring nCounter neuroinflammatory panel comprised of 770 genes. Histomorphological evaluation of muscle morphology and composition was also performed. Our findings suggest that while prenatal THC exposure had narrow overall effects on fetal and infant muscle development, the greatest impacts were observed within pathways related to inflammation and cytokine signaling, which suggest the potential for tissue damage and atrophy. This pilot study establishes feasibility to evaluate neuroinflammation due to prenatal THC exposure and provides rationale for follow-on studies that explore the longer-term implications and functional consequences encountered by offspring as they continue to mature. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to explain the internal mechanism of attention focus affecting performance of countermovement jump based on muscle synergy theory. Methods: Participants involved untrained group(N = 10) and high-level group(N = 11). Subjects performed countermovement jump with internal attention focus instruction (IF), external distal attention focus instruction (EDF), and external proximal attention focus instruction (EPF). The electromyography (EMG) signals of the dominant vastus lateralis muscle (VL), semitendinosus muscle (ST), tibial anterior muscle (TA), rectus femoris muscle (RF), and medial gastrocnemius (MG) were recorded. The non-negative matrix factorization was used to extract muscle synergy. Results: 1) Attention focus did not affect countermovement jump performance and the number of muscle synergy in the high-level group (P>0.05). 2) Attention focus instructions affected the untrained group countermovement jump (P<0.05). and EDF and EPF reduced the number of muscle synergy. 3)The Cohen's d of EDF (0.269) was less than EPF (0.377) in untrained group. Conclusion: For the untrained people, the improved motor performance caused by attention focus resembled the adaptive changes that occur with long-term training. The reason why an EDF is superior to EPF is that the former produces more thorough changes in muscle synergy. [ABSTRACT FROM AUTHOR]

Introduction: Although sloped surfaces are common in daily living, most studies of body balance are carried out on flat surfaces, and few data are available for sloping angles below 14°. Objectives: The purpose of this study was to explore the effect of forward and backward sloping surfaces at 7° and 15° on postural equilibrium and the activity of flexor/extensor ankle muscles. Methods: Fifteen healthy subjects (8 males and 7 females) (27.67 ± 3.9 years) underwent a posturographic examination associated with a surface electromyogram (EMG) of tibialis anterior (TA), soleus (Sol) and gastrocnemius medialis (GasM) under five conditions of support inclination: 0° (H0), backward inclination at 7° and 15° (DF7 and DF15), forward inclination at 7° and 15° (PF7 and PF15). Results: Results showed that the center of pressure (CP) was shifted according to the surface slope, with a forward move in PF7 (p <0.001) and PF15 (p <0.001) and a backward move in DF7 (p <0.01) and in DF15 (p <0.001). The mean displacement of the CP along the anterior-posterior axis (Xm) was increased in DF15 (p <0.01) relative to the H0 condition but reduced in PF7 (p <0.01). The normalized EMG revealed higher values when the muscles were in a shortened position (PF7 for Sol, p <0.05; PF15 for GasM, p <0.01; DF15 for TA, p<0.01) and lower values of GasM and Sol when lengthened (DF15, p <0.05). Conclusion: Our findings indicate that standing on a backward sloped surface impairs body balance, while low-angle forward sloped surfaces might improve postural stability. Muscular activity variations of the ankle flexors/extensors, which are stretched or shortened, also seem to be related to the length-tension relationship of skeletal muscles. [ABSTRACT FROM AUTHOR]

The human forearm model is commonly employed in physiological investigations exploring local vascular function and oxygen delivery; however, the effect of arm dominance on exercising forearm hemodynamics and skeletal muscle oxygen saturation (SmO2) in untrained individuals is poorly understood. Therefore, the purpose of this study was to explore the effect of self-identified arm dominance on forearm hemodynamics and SmO2 in untrained individuals during submaximal, non-ischemic forearm exercise. Twenty healthy individuals (23±4 years, 50% female; 80% right-handed) completed three-minute bouts of supine rhythmic (1 second contraction: 2 second relaxation duty cycle) forearm handgrip exercise at both absolute (10kg; 98N) and relative (30% of maximal voluntary contraction) intensities in each forearm. Beat-by-beat measures of forearm blood flow (FBF; ml/min), mean arterial blood pressure (MAP; mmHg) and flexor digitorum superficialis SmO2 (%) were obtained throughout and averaged during the final 30 seconds of rest, exercise, and recovery while forearm vascular conductance was calculated (FVC; ml/min/100mmHg). Data are Δ from rest (mean±SD). Absolute force production did not differ between non-dominant and dominant arms (97±11 vs. 98±13 N, p = 0.606) whereas relative force production in females did (69±24 vs. 82±25 N, p = 0.001). At both exercise intensities, FBFRELAX, FVCRELAX, MAPRELAX, and the time constant tau for FBF and SmO2 were unaffected by arm dominance (all p>0.05). While arm dominance did not influence SmO2 during absolute intensity exercise (p = 0.506), the non-dominant arm in females experienced an attenuated reduction in SmO2 during relative intensity exercise (-14±10 vs. -19±8%, p = 0.026)–though exercise intensity was also reduced (p = 0.001). The present investigation has demonstrated that arm dominance in untrained individuals does not impact forearm hemodynamics or SmO2 during handgrip exercise. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is characterized by a decrease in muscle mass and strength caused by an imbalance in protein synthesis and degradation. This process naturally occurs upon reduced or absent physical activity, often related to illness, forced bed rest, or unhealthy lifestyles. Currently, no treatment is available for atrophy, and it can only be prevented by overloading exercise, causing severe problems for patients who cannot exercise due to chronic diseases, disabilities, or being bedridden. The two murine models commonly used to induce muscle atrophy are hindlimb suspension and ankle joint immobilization, both of which come with criticalities. The lack of treatments and the relevance of this atrophic process require a unilateral, safe, and robust model to induce muscle atrophy. In this work, we designed and developed a 3D-printed cast to be used for the study of disuse skeletal muscle atrophy. Applying two halves of the cast is non-invasive, producing little to no swelling or skin damage. The application of the cast induces, in 2-weeks immobilized leg, the activation of atrophy-related genes, causing a muscle weight loss up to 25% in the gastrocnemius muscle, and 31% in the soleus muscle of the immobilized leg compared to the control leg. The cross-sectional area of the fibers is decreased by 31% and 34% respectively, with a peculiar effect on fiber types. In the immobilized gastrocnemius, absolute muscle force is reduced by 38%, while normalized force is reduced by 16%. The contralateral leg did not show signs of overload or hypertrophy when compared to free roaming littermates, offering a good internal control over the immobilized limb. Upon removing the cast, the mice effectively recovered mass and force in 3 weeks. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with type 1 diabetes (T1D) experience a complex set of alterations to skeletal muscle metabolic, neuromuscular, and vascular health; collectively referred to as diabetic myopathy. While the full scope of diabetic myopathy is still being elucidated, evidence suggests that even when individuals with T1D are physically active, indices of myopathy still exist. As such, there is a question if adherence to current physical activity guidelines elicits improvements in skeletal muscle health indices similarly between individuals with and without T1D. The objectives of this trial are to: 1) compare baseline differences in skeletal muscle health between adults with and without T1D, 2) examine the association between participation in a home-based exercise program, detraining, and retraining, with changes in skeletal muscle health, and 3) examine the roles of age and sex on these associations. Methods and analysis: This will be a prospective interventional trial. Younger (18–30 years) and older (45–65 years) males and females with T1D and matched individuals without T1D will engage in a four-phase, 18-week study sequentially consisting of a one-week lead-in period, 12-week exercise training program, one-week detraining period, and four-week retraining period. The exercise program will consist of aerobic and resistance exercise based on current guidelines set by Diabetes Canada. Metabolic, neuromuscular, and vascular outcome measures will be assessed four times: at baseline, post-exercise program, post-detraining, and post-retraining. Differences in baseline metrics between those with and without T1D will be examined with independent sample t-tests, and with two-way analyses of variance for age- and sex-stratified analyses. Changes across the duration of the study will be examined using mixed-model analyses. Dissemination: Findings from this research will be shared locally and internationally with research participants, clinicians, diabetes educators, and patient advocacy organizations via in-person presentations, social media, and scientific fora. Trial registration number: NCT05740514. [ABSTRACT FROM AUTHOR]

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase 2 (GPX2) is a selenium-dependent enzyme and protects cells against oxidative damage. Recently, GPX2 has been identified as a candidate gene for backfat and feed efficiency in pigs. However, it is unclear whether GPX2 regulates the development of porcine preadipocytes and skeletal muscle cells. In this study, adenoviral gene transfer was used to overexpress GPX2. Our findings suggest that overexpression of GPX2 gene inhibited proliferation of porcine preadipocytes. And the process is accompanied by the reduction of the p-p38. GPX2 inhibited adipogenic differentiation and promoted lipid degradation, while ERK1/2 was reduced and p-p38 was increased. Proliferation of porcine skeletal muscle cells was induced after GPX2 overexpression, was accompanied by activation in JNK, ERK1/2, and p-p38. Overexpression methods confirmed that GPX2 has a promoting function in myoblastic differentiation. ERK1/2 pathway was activated and p38 was suppressed during the process. This study lays a foundation for the functional study of GPX2 and provides theoretical support for promoting subcutaneous fat reduction and muscle growth. [ABSTRACT FROM AUTHOR]

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors. Methods: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass. Discussion: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups. [ABSTRACT FROM AUTHOR]

Malnutrition after stroke may lessen the beneficial effects of rehabilitation on motor recovery through influences on both brain and skeletal muscle. Enriched rehabilitation (ER), a combination of environmental enrichment and forelimb reaching practice, is used preclinically to study recovery of skilled reaching after stroke. However, the chronic food restriction typically used to motivate engagement in reaching practice is a barrier to using ER to investigate interactions between nutritional status and rehabilitation. Thus, our objectives were to determine if a modified ER program comprised of environmental enrichment and skilled reaching practice motivated by a short fast would enhance post-stroke forelimb motor recovery and preserve forelimb muscle size and metabolic fiber type, relative to a group exposed to stroke without ER. At one week after photothrombotic cortical stroke, male, Sprague-Dawley rats were assigned to modified ER or standard care for 2 weeks. Forelimb recovery was assessed in the Montoya staircase and cylinder task before stroke and on days 5–6, 22–23, and 33–34 after stroke. ER failed to improve forelimb function in either task (p > 0.05). Atrophy of extensor digitorum communis (EDC) and triceps brachii long head (TBL) muscles was not evident in the stroke-targeted forelimb on day 35, but the area occupied by hybrid fibers was increased in the EDC muscle (p = 0.038). ER bilaterally increased EDC (p = 0.046), but not TBL, muscle size; EDC muscle fiber type was unchanged by ER. While the modified ER did not promote forelimb motor recovery, it does appear to have utility for studying the role of skeletal muscle plasticity in post-stroke recovery. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass and density, as assessed by CT-body composition (CT-BC), are recognised to have prognostic value in non-cancer and cancer patients. The aim of the present study was to compare CT-BC parameters between non-cancer (abdominal aortic aneurysm, AAA) and cancer (colorectal cancer, CRC) patients. Methods: Two retrospective multicentre cohorts were compared. Thresholds of visceral fat area (VFA, Doyle), skeletal fat index (SFI, Ebadi), skeletal muscle index (SMI, Martin), and skeletal muscle density (SMD, Martin) were applied to these cohorts and compared. The systemic inflammatory response (SIR) was measured by the systemic inflammatory grade (SIG). Results: 1695 patients were included; 759 patients with AAA and 936 patients with CRC. Low SMD (33% vs. 66%, p <0.001) was more prevalent in the CRC cohort. Low SMI prevalence was similar in both cohorts (51% vs. 51%, p = 0.80). Compared with the AAA cohort, the CRC cohort had a higher prevalence of raised SIG (p <0.001). Increasing age (OR 1.54, 95% CI 1.38–1.72, p < 0.001) and elevated SIG (OR 1.23, 95% CI 1.09–1.40, p = 0.001) were independently associated with increased odds of low SMI. Increasing age (OR 1.90, 95% CI 1.66–2.17, p < 0.001) CRC diagnosis (OR 5.89, 95% CI 4.55–7.62, p < 0.001), ASA > 2 (OR 1.37, 95% CI 1.08–1.73, p = 0.01), and elevated SIG (OR 1.19, 95% CI 1.03–1.37, p = 0.02) were independently associated with increased odds of low SMD. Conclusions: Increasing age and systemic inflammation appear to be important determinants of loss of skeletal muscle mass and quality irrespective of disease. [ABSTRACT FROM AUTHOR]

Mechanical overloading (OVL) resulting from the ablation of muscle agonists, a supra-physiological model of resistance training, reduces skeletal muscle fragility, i.e. the immediate maximal force drop following lengthening contractions, and increases maximal force production, in mdx mice, a murine model of Duchene muscular dystrophy (DMD). Here, we further analyzed these beneficial effects of OVL by determining whether they were blocked by cyclosporin, an inhibitor of the calcineurin pathway, and whether there were also observed in the D2-mdx mice, a more severe murine DMD model. We found that cyclosporin did not block the beneficial effect of 1-month OVL on plantaris muscle fragility in mdx mice, nor did it limit the increases in maximal force and muscle weight (an index of hypertrophy). Fragility and maximal force were also ameliorated by OVL in the plantaris muscle of D2-mdx mice. In addition, OVL increased the expression of utrophin, cytoplamic γ-actin, MyoD, and p-Akt in the D2-mdx mice, proteins playing an important role in fragility, maximal force gain and muscle growth. In conclusion, OVL reduced fragility and increased maximal force in the more frequently used mild mdx model but also in D2-mdx mice, a severe model of DMD, closer to human physiopathology. Moreover, these beneficial effects of OVL did not seem to be related to the activation of the calcineurin pathway. Thus, this preclinical study suggests that resistance training could have a potential benefit in the improvement of the quality of life of DMD patients. [ABSTRACT FROM AUTHOR]

Prolonged sedentary behaviour (SB) i.e. longer bouts, is suggested to have a range of negative health effects, independent of habitual light and medium-to-vigorous physical activity (LIPA or MVPA). Any effect on musculoskeletal size, architecture or morphology has seldom been reported in older adults. Moreover, no study has yet determined if any association would persist following adjustment for covariates. Therefore, the aim of the present study was to investigate the associations between SB, and properties of the Gastrocnemius Medialis (GM) muscle, in a cross-sectional sample of older adults using compositional data analysis. 105 healthy older adults (73±6y) wore a thigh mounted tri-axial accelerometer for seven consecutive days, and underwent ultrasound [e.g. muscle length (Lm), anatomical cross-sectional area (ACSA), muscle volume (VM), fascicle length (LF), & physiological cross-sectional area (PCSA)], body composition (e.g. DEXA) and health (e.g. medical history) assessments. In-unadjusted models, SB time was negatively associated with ACSA at 75% of Lm (R2adj = 0.085), VM (R2adj = 0.020), and PCSA (R2adj = 0.039). Standing was positively associated with pennation angle (R2adj = 0.110), which persisted following co-variate adjustment (R2adj = 0.296). In fully adjusted models, both SB & LIPA time were associated with ACSA at 75% of Lm (Both R2adj = 0.393). Standing and light activity time were also associated with LF, VM, & PCSA (R2adj 0.116–0.573). In fully adjusted models, SB pattern parameters (i.e. the manner in which sedentary behaviour is accumulated daily throughout waking hours such as the timing, duration and frequency of sedentary bouts), were associated with GM muscle properties (R2adj 0.156–0.564) including LM, LF, and VM. The pattern, rather than accumulated daily SB time, was associated with the size and architecture of the GM. Our results suggest that regardless of co-existing habitual physical activities, SB bouts should be kept short and frequently interrupted to offset some of the deleterious ageing-related muscle architecture characteristics changes. [ABSTRACT FROM AUTHOR]

Background: Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship. Methods: C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups. Results: Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios. Conclusions: Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia. [ABSTRACT FROM AUTHOR]

We investigated the differences in quantity and quality of skeletal muscle between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) individuals using abdominal CT. One hundred and seventy-two people with morbid obesity who underwent bariatric surgery and 64 healthy control individuals participated in this retrospective study. We divided the people with morbid obesity into an MHO and MUO group. In addition, nonobese metabolic healthy people were included analysis to provide reference levels. CT evaluation of muscle quantity (at the level of the third lumbar vertebra [L3]) was performed by calculating muscle anatomical cross-sectional area (CSA), which was normalized to patient height to produce skeletal muscle index (SMI). Muscle quality was assessed as skeletal muscle density (SMD), which was calculated from CT muscle attenuation. To characterize intramuscular composition, muscle attenuation was classified into three categories using Hounsfield unit (HU) thresholds: -190 HU to -30 HU for intermuscular adipose tissue (IMAT), -29 to +29 HU for low attenuation muscle (LAM), and +30 to +150 HU for normal attenuation muscle (NAM). People with morbid obesity comprised 24 (14%) MHO individuals and 148 (86%) MUO individuals. The mean age of the participants was 39.7 ± 12.5 years, and 154 (65%) participants were women. MUO individuals had a significantly greater total skeletal muscle CSA than MHO individuals in the model that adjusted for all variables. Total skeletal muscle SMI, SMD, NAM index, LAM index, and IMAT index did not differ between MHO and MUO individuals for all adjusted models. Total skeletal muscle at the L3 level was not different in muscle quantity, quality, or intramuscular composition between the MHO and MUO individuals, based on CT evaluation. MHO individuals who are considered "healthy" should be carefully monitored and can have a similar risk of metabolic complications as MUO individuals, at least based on an assessment of skeletal muscle. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) is the second most common neurodegenerative disease behind Alzheimer's Disease, currently affecting more than 10 million people worldwide and 1.5 times more males than females. The progression of PD results in the loss of function due to neurodegeneration and neuroinflammation. The etiology of PD is multifactorial, including both genetic and environmental origins. Here we explored changes in RNA editing, specifically editing through the actions of the Adenosine Deaminases Acting on RNA (ADARs), in the progression of PD. Analysis of ADAR editing of skeletal muscle transcriptomes from PD patients and controls, including those that engaged in a rehabilitative exercise training program revealed significant differences in ADAR editing patterns based on age, disease status, and following rehabilitative exercise. Further, deleterious editing events in protein coding regions were identified in multiple genes with known associations to PD pathogenesis. Our findings of differential ADAR editing complement findings of changes in transcriptional networks identified by a recent study and offer insights into dynamic ADAR editing changes associated with PD pathogenesis. [ABSTRACT FROM AUTHOR]

This article discusses concerns that were raised about the reuse of data from a previous study by some of the same authors. The study in question appears to overlap with the earlier work in terms of methodology, results, and conclusions. Additionally, some images in the article are based on the same tissue samples as the previous study, but this was not declared. The corresponding author has provided explanations for some of the similarities, but the Editorial Board determined that the extent of the overlap and the undeclared reuse of data warrant a retraction of the article. There are also unresolved issues regarding the study's ethical approval, funding statement, and references to "Data not shown." Certain figures in the article have been excluded from the republished version due to licensing restrictions. [Extracted from the article]

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NP), including atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), play essential roles in regulating blood pressure, cardiovascular homeostasis, and systemic metabolism. One of the major metabolic effects of NP is manifested by their capacity to stimulate lipolysis and the thermogenesis gene program in adipocytes, however, in skeletal muscle their effects on metabolism and muscle function are not as well understood. There are three NP receptors (NPR): NPRA, NPRB, and NPRC, and all three NPR genes are expressed in skeletal muscle and C2C12 myocytes. In C2C12 myocytes treatment with either ANP, BNP, or CNP evokes the cGMP signaling pathway. Since NPRC functions as a clearance receptor and the amount of NPRC in a cell type determines the signaling strength of NPs, we generated a genetic model with Nprc gene deletion in skeletal muscle and tested whether enhancing NP signaling by preventing its clearance in skeletal muscle would improve exercise performance in mice. Under sedentary conditions, Nprc skeletal muscle knockout (MKO) mice showed comparable exercise performance to their floxed littermates in terms of maximal running velocity and total endurance running time. Eight weeks of voluntary running-wheel training in a young cohort significantly increased exercise performance, but no significant differences were observed in MKO compared with floxed control mice. Furthermore, 6-weeks of treadmill training in a relatively aged cohort also increased exercise performance compared with their baseline values, but again there were no differences between genotypes. In summary, our study suggests that NP signaling is potentially important in skeletal myocytes but its function in skeletal muscle in vivo needs to be further studied in additional physiological conditions or with new genetic mouse models. [ABSTRACT FROM AUTHOR]

The healthy benefits of regular physical exercise are mainly mediated by the stimulation of oxidative and antioxidant capacities in skeletal muscle. Our understanding of the cellular and molecular responses involved in these processes remain often uncomplete particularly regarding muscle typology. The main aim of the present study was to compare the effects of two types of exercise training protocol: a moderate-intensity continuous training (MICT) and a high-intensity interval training (HIIT) on metabolic processes in two muscles with different typologies: soleus and extensor digitorum longus (EDL). Training effects in male Wistar rats were studied from whole organism level (maximal aerobic speed, morphometric and systemic parameters) to muscle level (transcripts, protein contents and enzymatic activities involved in antioxidant defences, aerobic and anaerobic metabolisms). Wistar rats were randomly divided into three groups: untrained (UNTR), n = 7; MICT, n = 8; and HIIT, n = 8. Rats of the MICT and HIIT groups ran five times a week for six weeks at moderate and high intensity, respectively. HIIT improved more than MICT the endurance performance (a trend to increased maximal aerobic speed, p = 0.07) and oxidative capacities in both muscles, as determined through protein and transcript assays (AMPK–PGC-1α signalling pathway, antioxidant defences, mitochondrial functioning and dynamics). Whatever the training protocol, the genes involved in these processes were largely more significantly upregulated in soleus (slow-twitch fibres) than in EDL (fast-twitch fibres). Solely on the basis of the transcript changes, we conclude that the training protocols tested here lead to specific muscular responses. [ABSTRACT FROM AUTHOR]

Early detection of skeletal muscle atrophy is important to prevent further muscle weakness. However, there are few non-invasive biomarkers for skeletal muscle atrophy. Recent studies have reported that the N-terminal fragment (N-titin) of titin, a giant sarcomeric protein, is detected in the urine of patients with muscle damage. In this study, we hypothesized that urinary N-titin would be a potential early biomarker of skeletal muscle atrophy in mice caused by sciatic nerve denervation. Male mice were randomly divided into control and denervation groups, and urinary N-titin levels were assessed daily for 9 days using an enzyme-linked immunosorbent assay system. Despite reduced titin protein levels in atrophic muscles 10 days after denervation, cleaved N-titin fragments were not increased in the urine of mice with denervation-induced muscle atrophy. Furthermore, we found no uptake of Evans blue dye from the extracellular space into the cytoplasm in atrophic muscles, suggesting that the sarcomeric membrane is intact in those muscles. The present results suggest that cleaved N-titin in the urine is not suitable as an early biomarker of skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

The skeletal muscles of Type II diabetic (T2D) patients can be characterized by a reduced vessel density, corresponding to deficiencies in microvascular angiogenesis. Interestingly, T2D also inhibits the function of many myogenic cells resident within skeletal muscle, including satellite cells, which are well-known for the role they play in maintaining homeostasis. The current study was undertaken to gain a better understanding of the mechanisms whereby satellite cell progeny, muscle precursor cells (MPCs), influence microvascular angiogenesis. Network growth and the expression of genes associated with angiogenesis were reduced when microvessels were treated with conditioned media generated by proliferating MPCs isolated from diabetic, as compared to control rat skeletal muscle, a phenomenon that was also observed when myoblasts from control or diabetic human skeletal muscle were used. When only exosomes derived from diabetic or control MPCs were used to treat microvessels, no differences in microvascular growth were observed. An evaluation of the angiogenesis factors in control and diabetic MPCs revealed differences in Leptin, vascular endothelial growth factor (VEGF), IL1-β, interleukin 10, and IP-10, and an evaluation of the MPC secretome revealed differences in interleukin 6, MCP-1, VEGF, and interleukin 4 exist. Angiogenesis was also reduced in tissue-engineered skeletal muscles (TE-SkM) containing microvessels when they were generated from MPCs isolated from diabetic as compared to control skeletal muscle. Lastly, the secretome of injured control, but not diabetic, TE-SkM was able to increase VEGF and increase microvascular angiogenesis. This comprehensive analysis of the interaction between MPCs and microvessels in the context of diabetes points to an area for alleviating the deleterious effects of diabetes on skeletal muscle. [ABSTRACT FROM AUTHOR]

Background: It is widely acknowledged that eccentric muscle contractions may cause skeletal muscle damage. However, there is little knowledge about the impact of eccentric contractions on non-muscular structures. Animal and human studies revealed that eccentric contractions can also induce immediate and short-term nerve dysfunction. The purpose of this review is to examine whether eccentric muscle contractions induce immediate and short-term effects on structural, morphological, mechanical, functional and physiological properties of peripheral nerves, from both animal and human studies. Methods and analysis: A systematic review of randomised (RCTs) and non-randomised controlled trials will be conducted. Four electronic databases (i.e., Medline/Pubmed, Science Direct, PEDro and Cochrane) will be searched using predefined search terms to identify relevant studies. Eligible studies have to comprise any type of eccentric contraction of upper or lower limb muscles. Primary outcomes will include measures related to structure, morphology, mechanical, functional and physiological properties of peripheral nerves. Two independent reviewers will assess eligibility, evaluate risk of bias, and extract relevant data. In human studies, the risk of bias will be assessed by the Cochrane Collaboration risk of bias tool (RoB 2.0 tool) for RCTs and by risk of bias in non-randomised studies of interventions (ROBINS-I) for non-randomised controlled trials; while for animal studies, the risk of bias will be assessed using the SYRCLE's RoB tool. A narrative synthesis will be conducted for all included studies. Also, if appropriate, a meta-analysis will be performed, where the effect size of each outcome will be determined by the standardized mean difference as well as the 95% confidence intervals. I2 statistics will be used to assess heterogeneity. Ethics and dissemination: For this study, no ethical approval is required. Findings will be disseminated widely through peer-reviewed publication and conference presentations. Systematic review registration: The protocol has been registered at the International Prospective Register of Systematic Reviews (PROSPERO). Registration number: CRD42021285767. [ABSTRACT FROM AUTHOR]

High-resolution respirometry methods allow for the assessment of oxygen consumption by the electron transfer systems within cells, tissue samples, and isolated mitochondrial preparations. As mitochondrial integrity is compromised by the process of cryopreservation, these methods have been limited to fresh samples. Here we present a simple method to assess the activity of mitochondria respiratory complexes I and II in previously cryopreserved murine skeletal muscle tissue homogenates, as well as previously frozen D. melanogaster, as a function of oxygen consumption. [ABSTRACT FROM AUTHOR]

Chronic skeletal muscle degeneration is characterized by fiber atrophy accompanied by deposition of extracellular matrix (ECM) components and fatty infiltration. Excessive accumulation of ECM leads to fibrosis via the contribution of fibro-adipogenic precursors (FAPs). Fibrosis also accompanies disuse atrophy and sarcopenia without significant inflammation. The present study aimed to comparatively analyze heterogeneous population of FAPs during acute injury and immobilization (tenotomy and denervation). The comparative analysis was accomplished based on the following 3 stromal cell subpopulations: i) CD140a(+)/Sca1(+); ii) CD140a(+)/Sca1(–); iii) CD140a(–)/Sca1(+). RNASeq analysis was employed to characterize and compare their quiescent and activated states. Whereas CD140a(-)/Sca1(+) was the most predominant activated subpopulation in tenotomy, denervation stimulated the CD140a(+)/Sca1(+) subpopulation. Immobilization models lacked myofiber damage and exhibited a minute increase in CD45(+) cells, as compared to acute injury. Transcriptome analysis showed common and discordant regulation of ECM components, without profound proliferative activation. Herein, we suggest unique surface markers for further identification of the investigated cell subpopulations. FAP subpopulations show similar activation kinetics in an inflammatory environment but the present findings highlight the fact that inflammation may not be a prerequisite for FAP activation. Delayed proliferation kinetics indicate that signals beyond inflammation might trigger FAP activation, leading to irreversible stromal changes. [ABSTRACT FROM AUTHOR]

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis. [ABSTRACT FROM AUTHOR]

Purpose: To identify the predictive role of pretreatment skeletal muscle mass index (SMI) for long-term survival of bladder cancer patients. Methods: Several databases were searched for studies investigating the relationship between pretreatment SMI and prognosis in bladder cancer. The overall survival (OS) and cancer-specific survival (CSS) were defined as primary and secondary outcomes, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were combined. Results: Nine studies involving 1476 cases were included. The results demonstrated that a lower pretreatment SMI was significantly related to poorer OS (HR = 1.56, 95% CI: 1.33–1.82, P<0.001) and subgroup analysis based on thresholds of SMI revealed similar results. Besides, pretreatment SMI was also obviously related to CSS (HR = 1.75, 95% CI: 1.36–2.25, P<0.001). Conclusion: Lower pretreatment SMI was associated with worse long-term survival of bladder cancer patients. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) causes sarcopenia and osteoporosis. However, the mechanisms underlying muscle and bone loss as well as the interactions between muscle and bone in the COPD state remain unclear. Therefore, we herein investigated the effects of the COPD state on muscle and bone in mice intratracheally administered porcine pancreatic elastase (PPE). The intratracheal administration of PPE to mice significantly reduced trabecular bone mineral density (BMD), trabecular bone volume, trabecular number, cortical BMD and cortical area. It also significantly decreased grip strength, but did not affect muscle mass or the expression of myogenic differentiation-, protein degradation- or autophagy-related genes in the soleus and gastrocnemius muscles. Among the myokines examined, myostatin mRNA levels in the soleus muscles were significantly elevated in mice treated with PPE, and negatively related to grip strength, but not bone parameters, in mice treated with or without 2 U PPE in simple regression analyses. Grip strength positively related to bone parameters in mice treated with or without PPE. In conclusion, we showed that a PPE model of COPD in mice exerts dominant effects on bone rather than skeletal muscles. Increased myostatin expression in the soleus muscles of mice in the COPD state may negatively relate to a reduction in grip strength, but not bone loss. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a challenging and progressive metabolic disease caused by insulin resistance. Skeletal muscle is the major insulin-sensitive tissue that plays a pivotal role in blood sugar homeostasis. Dysfunction of muscle metabolism is implicated in the disturbance of glucose homeostasis, the development of insulin resistance, and T2DM. Understanding metabolism reprogramming in newly diagnosed patients provides opportunities for early diagnosis and treatment of T2DM as a challenging disease to manage. Here, we applied a system biology approach to investigate metabolic dysregulations associated with the early stage of T2DM. We first reconstructed a human muscle-specific metabolic model. The model was applied for personalized metabolic modeling and analyses in newly diagnosed patients. We found that several pathways and metabolites, mainly implicating in amino acids and lipids metabolisms, were dysregulated. Our results indicated the significance of perturbation of pathways implicated in building membrane and extracellular matrix (ECM). Dysfunctional metabolism in these pathways possibly interrupts the signaling process and develops insulin resistance. We also applied a machine learning method to predict potential metabolite markers of insulin resistance in skeletal muscle. 13 exchange metabolites were predicted as the potential markers. The efficiency of these markers in discriminating insulin-resistant muscle was successfully validated. [ABSTRACT FROM AUTHOR]

Objective: The relationship between low skeletal muscle mass index (SMI) and all-cause mortality risk in the general adults remains unclear. Our study was conducted to examine and quantify the associations between low SMI and all-cause mortality risks. Methods: PubMed, Web of Science, and Cochrane Library for primary data sources and references to relevant publications retrieved until 1 April 2023. A random-effect model, subgroup analyses, meta-regression, sensitivity analysis, and publication bias were conducted using STATA 16.0. Results: Sixteen prospective studies were included in the meta-analysis of low SMI and the risk of all-cause mortality. A total of 11696 deaths were ascertained among 81358 participants during the 3 to 14.4 years follow-up. The pooled RR of all-cause mortality risk was 1.57 (95% CI, 1.25 to 1.96, P < 0.001) across the lowest to the normal muscle mass category. The results of meta-regression showed that BMI (P = 0.086) might be sources of heterogeneity between studies. Subgroup analysis showed that low SMI was significantly associated with an increased risk of all-cause mortality in studies with a body mass index (BMI) between 18.5 to 25 (1.34, 95% CI, 1.24–1.45, P<0.001), 25 to 30 (1.91, 95% CI, 1.16–3.15, P = 0.011), and over 30 (2.58, 95% CI, 1.20–5.54 P = 0.015). Conclusions: Low SMI was significantly associated with the increased risk of all-cause mortality, and the risk of all-cause mortality associated with low SMI was higher in adults with a higher BMI. Low SMI Prevention and treatment might be significant for reducing mortality risk and promoting healthy longevity. [ABSTRACT FROM AUTHOR]

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids with antagonistic inflammatory functions that play vital roles in metabolic health and immune response. Current commercial swine diets tend to over-supplement with n-6 PUFAs, which may increase the likelihood of developing inflammatory diseases and affect the overall well-being of the animals. However, it is still poorly understood how n-6/n-3 PUFA ratios affect the porcine transcriptome expression and how messenger RNAs (mRNAs) and microRNAs (miRNAs) might regulate biological processes related to PUFA metabolism. On account of this, we selected a total of 20 Iberian × Duroc crossbred pigs with extreme values for n-6/n-3 FA ratio (10 high vs 10 low), and longissimus dorsi muscle samples were used to identify differentially expressed mRNAs and miRNAs. The observed differentially expressed mRNAs were associated to biological pathways related to muscle growth and immunomodulation, while the differentially expressed microRNAs (ssc-miR-30a-3p, ssc-miR-30e-3p, ssc-miR-15b and ssc-miR-7142-3p) were correlated to adipogenesis and immunity. Relevant miRNA-to-mRNA regulatory networks were also predicted (i.e., mir15b to ARRDC3; mir-7142-3p to METTL21C), and linked to lipolysis, obesity, myogenesis, and protein degradation. The n-6/n-3 PUFA ratio differences in pig skeletal muscle revealed genes, miRNAs and enriched pathways involved in lipid metabolism, cell proliferation and inflammation. [ABSTRACT FROM AUTHOR]

Athletic conditioning can increase the capacity for insulin-stimulated skeletal muscle glucose uptake through increased sarcolemmal expression of GLUT4 and potentially additional novel glucose transporters. We used a canine model that has previously demonstrated conditioning-induced increases in basal, insulin- and contraction-stimulated glucose uptake to identify whether expression of glucose transporters other than GLUT4 was upregulated by athletic conditioning. Skeletal muscle biopsies were obtained from 12 adult Alaskan Husky racing sled dogs before and after a full season of conditioning and racing, and homogenates from those biopsies were assayed for expression of GLUT1, GLUT3, GLUT4, GLUT6, GLUT8, and GLUT12 using western blots. Athletic conditioning resulted in a 1.31 ± 0.70 fold increase in GLUT1 (p <0.0001), 1.80 ± 1.99 fold increase in GLUT4 (p = 0.005), and 2.46 ± 2.39 fold increase in GLUT12 (p = 0.002). The increased expression of GLUT1 helps explain the previous findings of conditioning-induced increases in basal glucose clearance in this model, and the increase in GLUT12 provides an alternative mechanism for insulin- and contraction-mediated glucose uptake and likely contributes to the substantial conditioning-induced increases in insulin sensitivity in highly trained athletic dogs. Furthermore, these results suggest that athletic dogs can serve as a valuable resource for the study of alternative glucose transport mechanisms in higher mammals. [ABSTRACT FROM AUTHOR]

Objectives: Muscle health is essential for children's physical development and future health. PPARGC1A gene encode the peroxisome proliferator-activated receptor coactivator 1α which coactivates transcription factors that control mediating skeletal muscle fiber type conversion and skeletal muscle fiber formation. The PPARGC1A rs8192678 Gly/Ser (Gly482Ser) polymorphism was associated with the regulation of skeletal muscle fibre type. This paper aims to explore the association between the PPARGC1A rs8192678 (Gly482Ser) polymorphism and muscle fitness in Chinese schoolchildren. Methods: We detected the distribution of the PPARGC1A rs8192678 (Gly482Ser) polymorphism by DNA typing of saliva samples from untrained Southern Chinese Han children aged 7–12 years. Considering that muscle studies in children cannot use invasive sampling, we analyzed the association between alleles and genotypes with high validity tests of muscle fitness assesment in children(handgrip strength, standing long jump, sit-ups and push-ups). Results: The results showed no significant differences in height, weight or body mass index between the sexes. The grip strength indicators were correlated with age in boys and height and weight in girls. Sit-ups were significantly higher in girls with the PPARGC1A Gly/Gly genotype than in boys, and handgrip strength and standing long jump were significantly lower in girls with the PPARGC1A rs8192678 (Gly482Ser) genotype than in boys. Genetic model analysis showed that the Gly482 allele had a dominant genetic effect on the Gly482 allele is hypothesized to influence the expression of type I fibers in skeletal muscle in girls, while the Ser482 allele affects on type II fibers in girls. The two alleles had little genetic effect on boys. Conclusions: The results suggested the possible association of the PPARGC1A rs8192678 (Gly482Ser) polymorphism on myofibril type-related phenotypes in Han Chinese children in southern China, with a particular impact on girls. [ABSTRACT FROM AUTHOR]

Background: Several tools exist to measure tightness of the gastrocnemius muscles; however, few of them are reliable enough to be used routinely in the clinic. The primary objective of this study was to evaluate the intra- and inter-rater reliability of a new equinometer. The secondary objective was to determine the load to apply on the plantar surface of the metatarsal heads to achieve the highest reliability when measuring gastrocnemius tightness. Methods: The equinometer consisted of a goniometer and an electronic dynamometer, hooked up to a computer. Three raters carried out three trials of passive dorsiflexion by applying controlled pressure to the metatarsal heads of both ankles in 29 healthy subjects under two experimental conditions: knee extended (KE) and knee flexed at 30 degrees (KF). The equinometer continuously recorded the ankle dorsiflexion values (in °) corresponding to each 1 N interval of plantar pressure between 4 N and 20 N. The intra- and inter-rater reliability of the ankle dorsiflexion were evaluated through the intra-class correlation (ICC) coefficients in each of the pressure intervals. Results: The intra-rater ICC in KE and KF was between 0.84 and 0.98. The inter-rater ICC in KE and KF was between 0.59 and 0.92. The pressure interval between 14 N and 15 N had the highest intra-rater (ICC = 1) and inter-rater reliability (0.87≤ICC≤0.99). A more refined analysis of this interval found that a load of 14.5 N yielded the best reliability. Conclusions: This compact equinometer has excellent intra-rater reliability and moderate to good inter-rater reliability. Since this reliability is optimal in the 14–15 N range, this load should be used going forward in clinical practice, especially when aiming to define a pathological threshold for tightness of the gastrocnemius muscles. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of age. Integration of RNA-seq, mass spectrometry-based metabolomic and lipidomic data obtained in muscle and blood samples by Multi-Omics Factor Analysis (MOFA) led to the identification of 8 latent factors that explained 78.8% of the variance in the multiomic dataset. Latent factors could discriminate dystrophic and healthy mice, as well as different time-points. MOFA enabled to connect the gene expression signature in dystrophic muscles, characterized by pro-fibrotic and energy metabolism alterations, to inflammation and lipid signatures in blood. Our results show that omic observations in blood can be directly related to skeletal muscle pathology in dystrophic muscle. [ABSTRACT FROM AUTHOR]

Previous evidence indicated that interventions with combined neuromuscular electrical stimulation (NMES) and voluntary muscle contractions could have superior effects on corticospinal excitability when the produced total force is larger than each single intervention. However, it is unclear whether the superior effects exist when the produced force is matched between the interventions. Ten able-bodied individuals performed three intervention sessions on separate days: (i) NMES–tibialis anterior (TA) stimulation; (ii) NMES+VOL–TA stimulation combined with voluntary ankle dorsiflexion; (iii) VOL–voluntary ankle dorsiflexion. Each intervention was exerted at the same total output of 20% of maximal force and applied intermittently (5 s ON / 19 s OFF) for 16 min. Motor evoked potentials (MEP) of the right TA and soleus muscles and maximum motor response (Mmax) of the common peroneal nerve were assessed: before, during, and for 30 min after each intervention. Additionally, the ankle dorsiflexion force-matching task was evaluated before and after each intervention. Consequently, the TA MEP/Mmax during NMES+VOL and VOL sessions were significantly facilitated immediately after the interventions started until the interventions were over. Compared to NMES, larger facilitation was observed during NMES+VOL and VOL sessions, but no difference was found between them. Motor control was not affected by any interventions. Although superior combined effects were not shown compared to voluntary contractions alone, low-level voluntary contractions combined with NMES resulted in facilitated corticospinal excitability compared to NMES alone. This suggests that the voluntary drive could improve the effects of NMES even during low-level contractions, even if motor control is not affected. [ABSTRACT FROM AUTHOR]

Background: The dose-limiting effect of CT-assessed low skeletal muscle mass (LSMM) measured at the level of the third cervical vertebra has been found in head and neck cancer patients receiving high-dose cisplatin chemoradiotherapy. The aim of this study was to investigate the predictive factors for dose-limiting toxicities (DLTs) using low-dose weekly chemoradiotherapy. Materials and methods: Head and neck cancer patients receiving definite chemoradiotherapy with weekly 40 mg/m2 body surface area (BSA) cisplatin or paclitaxel 45 mg/m2 BSA and carboplatin AUC2 were consecutively included and retrospectively analysed. Skeletal muscle mass was assessed using the muscle surface at the level of the third cervical vertebra in pretherapeutic CT scans. After stratification for LSMM DLT, acute toxicities and feeding status during the treatment were examined. Results: Dose-limiting toxicity was significantly higher in patients with LSMM receiving cisplatin weekly chemoradiotherapy. For paclitaxel/carboplatin, no significance regarding DLT and LSMM could be found. Patients with LSMM had significantly more dysphagia before treatment, although feeding tube placement before treatment was equal in patients with and without LSMM. Conclusions: LSMM is a predictive factor for DLT in head and neck patients treated with low-dose weekly chemoradiotherapy with cisplatin. For paclitaxel/carboplatin, further research must be carried out. [ABSTRACT FROM AUTHOR]

Tensiomyography (TMG) is a non-invasive method for measuring contractile properties of skeletal muscle that is increasingly being used in research and practice. However, the lack of standardization in measurement protocols mitigates the systematic use in sports medical settings. Therefore, this study aimed to investigate the effects of lower leg fixation and sensor location on TMG-derived parameters. Twenty-two male participants underwent TMG measurements on the m. biceps femoris (BF) in randomized order with and without lower leg fixation (fixed vs. non-fixed). Measurements were conducted at 50% of the muscle's length (BF-mid) and 10 cm distal to this (BF-distal). The sensor location affected the contractile properties significantly, both with and without fixation. Delay time (Td) was greater at BF-mid compared to BF-distal (fixed: 23.2 ± 3.2 ms vs. 21.2 ± 2.7 ms, p = 0.002; non-fixed: 24.03 ± 4.2 ms vs. 21.8 ± 2.7 ms, p = 0.008), as were maximum displacement (Dm) (fixed: 5.3 ± 2.7 mm vs. 3.5 ± 1.7 mm, p = 0.005; non-fixed: 5.4 ± 2.5 mm vs. 4.0 ± 2.0 mm, p = 0.03), and contraction velocity (Vc) (fixed: 76.7 ± 25.1 mm/s vs. 57.2 ± 24.3 mm/s, p = 0.02). No significant differences were revealed for lower leg fixation (all p > 0.05). In summary, sensor location affects the TMG-derived parameters on the BF. Our findings help researchers to create tailored measurement procedures in compliance with the individual goals of the TMG measurements and allow adequate interpretation of TMG parameters. [ABSTRACT FROM AUTHOR]

The measurement of skeletal muscle mass is essential for the diagnosis of sarcopenia. Muscle ultrasonography has emerged as a useful tool for evaluating sarcopenia because it can be used to assess muscle quality and quantity. This study investigated whether muscle ultrasonography is effective for estimating appendicular skeletal muscle mass (ASM) and screening for sarcopenia. This study prospectively enrolled 212 healthy volunteers aged 40–80 years. ASM was measured using the bioelectrical impedance analysis. Muscle thickness (MT) and echo-intensity (EI) were measured in four muscles (biceps brachii, BB; triceps brachii, TB; rectus femoris, RF; biceps femoris, BF) on the dominant hand. A hold-out cross-validation method was used to develop and validate the ASM prediction equation. In the model development group, the ASM prediction equations were deduced as follows: estimated ASM for men (kg) = 0.167 × weight (kg) + 0.228 × height (cm) + 0.143 × MT of BF (mm)– 0.822 × EI to MT ratio of BB– 28.187 (R2 = 0.830) and estimated ASM for women (kg) = 0.115 × weight + 0.215 × height (cm) + 0.139 × MT of RF–0.638 × EI to MT ratio of BB– 23.502 (R2 = 0.859). In the cross-validation group, the estimated ASM did not significantly differ from the measured ASM in both men (p = 0.775; intraclass correlation coefficient [ICC] = 0.948) and women (p = 0.516; ICC = 0.973). In addition, multiple logistic regression analysis revealed that the ratios of EI to MT in the BF and RF muscles in men and MT in the BB muscle in women could be valuable parameters for sarcopenia screening. Therefore, our study suggests that muscle ultrasound could be an effective tool for estimating ASM and screening sarcopenia. [ABSTRACT FROM AUTHOR]

Sodium Fluoride (NaF) can change the expression of skeletal muscle proteins. Since skeletal muscle is rich in mitochondrial and contractile (sarcomeric) proteins, these proteins are sensitive to the effects of NaF, and the changes are dose-and time-dependent. In the current study, we have analysed the effect of high concentration s of NaF (80ppm) on mouse skeletal muscle at two different time points, i.e., 15 days and 60 days. At the end of the experimental time, the animals were sacrificed, skeletal muscles were isolated, and proteins were extracted and subjected to bioinformatic (Mass Spectrometric) analysis. The results were analysed based on changes in different mitochondrial complexes, contractile (sarcomeric) proteins, 26S proteasome, and ubiquitin-proteasome pathway. The results showed that the mitochondrial proteins of complex I, II, III, IV and V were differentially regulated in the groups treated with 80ppm of NaF for 15 days and 60 days. The network analysis indicated more changes in mitochondrial proteins in the group treated with the higher dose for 15 days rather than 60 days. Furthermore, differential expression of (sarcomeric) proteins, downregulation of 26S proteasome subunits, and differential expression in proteins related to the ubiquitin-proteasome pathway lead to muscle atrophy. The differential expression might be due to the adaptative mechanism to counteract the deleterious effects of NaF on energy metabolism. Data are available via ProteomeXchange with identifier PXD035014. [ABSTRACT FROM AUTHOR]

This study aims to investigate the anti-inflammatory effects of moringa isothiocyanate-1 (MIC-1) extracted from seeds of Moringa oleifera Lam. in lipopolysaccharide (LPS)-induced inflammation models. MIC-1 decreased nitric oxide production and reduced the expression of pro-inflammatory markers (TNF-α, Ifn-α, IL-1β, IL-6) in C2C12 myoblasts. The daily oral treatment of MIC-1 (80 mg/kg) for three days significantly reduced the expression of pro-inflammatory markers in gastrocnemius muscle tissue of LPS-treated C57BL/6 male mice. Transcriptomic analysis provided further insights into the inhibitory effects of MIC-1 on the LPS-induced inflammation, which suggested that MIC-1 affects inflammation and immunity-related genes in myoblasts and skeletal muscle tissue. MIC-1 inhibited the nuclear accumulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the LPS-treated myoblasts. Our data support the hypothesis that the MIC-1's effects in the muscle cells are mediated through the inhibition of the NF-κB translocation in the nucleus, which, in turn, results in immunomodulating and anti-inflammatory responses at the gene expression levels. [ABSTRACT FROM AUTHOR]

Background: Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT; NCoR2) is a transcriptional corepressor (CoR) which has been recognized as an important player in the regulation of hepatic lipogenesis and in somatic development in mouse embryo. SMRT protein is also widely expressed in mouse connective tissues, for example adipocytes and muscle. We recently reported that mice with global deletion of SMRT develop significant obesity and muscle wasting which are independent from thyroid hormone (TH) signaling and thermogenesis. However, the tissue specific role of SMRT in skeletal muscle is still not clear. Methods: To clarify role of SMRT in muscle differentiation, we made myogenic C2C12 clones which lack SMRT protein (C2C12-SKO) by using CRISPR-Cas9. Wild-type C2C12 (C2C12-WT) and C2C12-SKO cells were cultured in differentiation medium, and the resulting gene and protein profiles were compared between the two cell lines both before and after differentiation. We also analyzed muscle tissues which were dissected from whole body SMRT knockout (KO) mice and their controls. Results: We found significant up-regulation of muscle specific β-oxidation markers; Peroxisome proliferator-activated receptor δ (PPARδ) and PPARγ coactivator-1α (PGC-1α) in the C2C12-SKO cells, suggesting that the cells had a similar gene profile to what is found in exercised rodent skeletal muscle. On the other hand, confocal microscopic analysis showed the significant loss of myotubes in C2C12-SKO cells similar to the morphology found in immature myoblasts. Proteomics analysis also confirmed that the C2C12-SKO cells had higher expression of markers of fibrosis (ex. Collagen1A1; COL1A1 and Fibroblast growth factor-2; FGF-2), indicating the up-regulation of Transforming growth factor-β (TGF-β) receptor signaling. Consistent with this, treatment with a specific TGF-β receptor inhibitor ameliorated both the defects in myotube differentiation and fibrosis. Conclusion: Taken together, we demonstrate that SMRT functions as a pivotal transcriptional mediator for both β-oxidation and the prevention for the fibrosis via TGF-β receptor signaling in the differentiation of C2C12 myoblasts. In contrast to the results from C2C12 cells, SMRT does not appear to play a role in adult skeletal muscle of whole body SMRT KO mice. Thus, SMRT plays a significant role in the differentiation of myoblasts. [ABSTRACT FROM AUTHOR]