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Abstract Background Advanced Hybrid Closed-Loop system (AHCL) has profoundly changed type 1 diabetes therapy. This study primarily aimed to assess the impact on Glycemia Risk Index (GRI) and other continuous glucose monitoring (CGM) metrics when switching from one of four insulin strategies to AHCL in type 1 adult patients. Methods A single-center, retrospective pre/post observational study; 198 patients (age 44.4 ± 12.7 years, 115 females/83 males, diabetes duration 24.7 ± 11.6 years, HbA1c 7.4 ± 1%), treated with different insulin therapies (MDI, CSII, SAP with PLGS, HCL) were assessed before and after switching to an AHCL (MiniMed 780G, Diabeloop Roche, Tandem Control-IQ) at 1, 3, 6, and 12 months. Mixed-effects multivariable regression models were used to estimate the mean pre/post variations at different time points, adjusted for potential confounders. Results A month after the switch, there was an improvement in CGM metrics and HbA1c for all patients: GRI −10.7, GMI −0.27%, CV −2.1%, TAR>250 −3.7%, TAR180-250 −5.6%, TIR + 9.7%, HbA1c −0.54% (all p 250 at T1 (for all p

ABSTRACT Objective: In the following years after the United States Preventive Service Task Force (USPSTF) recommendation against prostate cancer screening with PSA in 2012, several authors worldwide described an increase in higher grades and aggressive prostate tumors. In this scenario, we aim to evaluate the potential impacts of USPSTF recommendations on the functional and oncological outcomes in patients undergoing robotic-assisted radical prostatectomy (RARP) in a referral center. Material and Methods: We included 11396 patients who underwent RARP between 2008 and 2021. Each patient had at least a 12-month follow-up. The cohort was divided into two groups based on an inflection point in the outcomes at the end of 2012 and the beginning of 2013. The inflection point period was detected by Bayesian regression with multiple change points and regression with unknown breakpoints. We reported continuous variables as median and interquartile range (IQR) and categorical variables as absolute and relative percent frequencies. Results: Group 1 had 4760 patients, and Group 2 had 6636 patients, with a median follow-up of 109 and 38 months, respectively. In the final pathology, Group 2 had 9.5% increase in tumor volume, 24% increase on Gleason ≥ 4+3 (ISUP 3), and 18% increase on ≥ pT3. This translated to a 6% increase in positive surgical margins and 24% reduction in full nerve sparing in response to the worsening pathology. There was a significant decline in post-operative outcomes in Group 2, including a 12-month continence reduction of 9%, reduction in potency by 27%, and reduction of trifecta by 22%. Conclusions: The increasing number of high-risk patients has led to worse functional and oncologic outcomes. The initial rapid rise in PSM was leveled by the move towards more partial nerve sparing. Among some historical changes in prostate cancer diagnosis and management in the period of our study, the USPSTF recommendation coincided with worse outcomes of prostate cancer treatment in a population who could benefit from PSA screening at the appropriate time.

Objective: Placement of human placenta derived grafts during robotic-assisted radical prostatectomy (RARP) hastens the return of continence and potency. The long-term impact on the oncologic outcomes remains to be investigated. Our objective was to determine the oncologic outcomes of patients with dehydrated human amnion chorion membrane (dHACM) at RARP compared to a matched cohort. Methods: In a referral centre, from August 2013 to October 2019, 599 patients used dHACM in bilateral nerve-sparing RARP. We excluded patients with less than 12 months follow-up, simple prostatectomy, and unilateral nerve-sparing. Patients with dHACM (amnio group) were 529, and were propensity score matched 1:1 to 2465 patients without dHACM (non-amnio group) and a minimum follow-up of 36 months. At the time of RARP, dHACM was placed around the neurovascular bundle in the amnio group. Continuous and categorical variables in matched groups was tested by two-sample Kolmogorov-Smirnov test and Fisher's exact test respectively. Outcomes measured were biochemical recurrence (BCR), adjuvant and salvage therapy rates. Results: Propensity score matching resulted in two groups of 444 patients. Cumulative incidence functions for BCR did not show a difference between the groups (p=0.3). Patients in the non-amnio group required salvage therapy more frequently than the amnio group, particularly after partial nerve-sparing RARP (6.3% vs. 2.3%, p=0.001). Limitations are the absence of prospective randomization. Conclusion: The data suggest that using dHACM does not have a negative impact on BCR in patients. Outcomes of cancer specific and overall survival will require follow-up study to increase our understanding of these grafts’ impact on prostate cancer biology.

Background/Objectives: In children, an association exists between muscle and bone, as well as between physical activity and osteogenesis. Impact loading is a factor in increasing bone accrual during growth. In this work, we explored the muscle–bone association in girls exposed to long-term physical activity at different levels of impact loading. Methods: Four groups of girls aged 7–16 were considered. The curricular (C; n = 22) group only had curricular physical activity at school (2 h/w). In addition to curricular physical activity, the girls in the dance (D; n = 21), gymnastics at lower training (GL; n = 14), and gymnastics at higher training (GH; n = 20) groups had 2 h/w, 4 h/w, and 4 h/w < training ≤ 12 h/w additional physical activity, respectively, for at least one year. A visual analysis estimated the respective amounts of impact-loading activity. The bone mineral content (BMC), areal bone mineral density (aBMD), and fat-free soft tissue mass (FFSTM) were assessed with dual-energy X-ray absorptiometry. Results: The results showed that, after adjusting for several confounders, statistically significant correlations were present between muscle mass and several bone mineral variables. A regression analysis confirmed the correlation in the data, and showed the marginal role of other body composition variables and physical activity for predicting BMC and BMD. Conclusion: Skeletal muscle mass is a major determinant of the BMC and BMD of the TBLH, as well as of the Appendicular level, in girls exposed to different amounts of long-term impact-loading physical activity.

This study was designed to support the tactical decisions of wheelchair basketball (WB) coaches in identifying the best players to form winning lineups. Data related to a complete regular season of a top-level WB Championship were examined. By analyzing game-related statistics from the first round, two clusters were identified that accounted for approximately 35% of the total variance. Cluster 1 was composed of low-performing athletes, while Cluster 2 was composed of high-performing athletes. Based on data related to the second round of the Championship, we conducted a two-fold evaluation of the clusters identified in the first round with the team's net performance as the outcome variable. The results showed that teams where players belonging to Cluster 2 had played more time during the second round of the championship were also those with the better team performance (R-squared = 0.48, p = 0.035), while increasing the playing time for players from Classes III and IV does not necessarily improve team performance (r2 = -0.14, p = 0.59). These results of the present study suggest that a collaborative approach between coaches and data scientists would significantly advance this Paralympic sport.

The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.

Here, the authors identify a novel regulator of autophagy, skeletal muscle mass and integrity named MYTHO. Silencing MYTHO protects against muscle atrophy in a wide range of acute catabolic conditions, while prolonged silencing causes a severe myopathy.

Marchioretti and colleagues show that in the skeletal muscle of SBMA mice and patients there is an early, but reversible alteration of expression of genes involved in muscle contraction and of mitochondrial respiration, followed by accumulation of calcium inside the mitochondria, which is concomitant with the onset of motor dysfunction, and late alteration of muscle structure.

Abstract Background Inactivity and unloading induce skeletal muscle atrophy, loss of strength and detrimental metabolic effects. Bed rest is a model to study the impact of inactivity on the musculoskeletal system. It not only provides information for bed‐ridden patients care, but it is also a ground‐based spaceflight analogue used to mimic the challenges of long space missions for the human body. In both cases, it would be desirable to develop a panel of biomarkers to monitor muscle atrophy in a minimally invasive way at point of care to limit the onset of muscle loss in a personalized fashion. Methods We applied mass spectrometry‐based proteomics to measure plasma protein abundance changes in response to 10 days of bed rest in 10 young males. To validate the correlation between muscle atrophy and the significant hits emerging from our study, we analysed in parallel, with the same pipeline, a cohort of cancer patients with or without cachexia and age‐matched controls. Our analysis resulted in the quantification of over 500 proteins. Results Unloading affected plasma concentration of proteins of the complement cascade, lipid carriers and proteins derived from tissue leakage. Among the latter, teneurin‐4 increased 1.6‐fold in plasma at bed rest day 10 (BR10) compared with BR0 (6.E9 vs. 4.3E9, P = 0.02) and decreased to 0.6‐fold the initial abundance after 2 days of recovery at normal daily activity (R + 2, 2.7E9, P = 3.3E‐4); the extracellular matrix protein lumican was decreased to 0.7‐fold (1.2E9 vs. 8.5E8, P = 1.5E‐4) at BR10 and remained as low at R + 2. We identified six proteins distinguishing subjects developing unloading‐mediated muscle atrophy (decrease of >4% of quadriceps cross‐sectional area) from those largely maintaining their initial muscle mass. Among them, transthyretin, a thyroid hormone‐binding protein, was significantly less abundant at BR10 in the plasma of subjects with muscle atrophy compared with those with no atrophy (1.6E10 vs. 2.6E10, P = 0.001). Haptoglobin‐related protein was also significantly reduced in the serum of cancer patients with cachexia compared with that of controls. Conclusions Our findings highlight a combination or proteomic changes that can be explored as potential biomarkers of muscle atrophy occurring under different conditions. The panel of significant proteomic differences distinguishing atrophy‐prone and atrophy‐resistant subjects after 10 days of bed rest need to be tested in a larger cohort to validate their potential to predict inactivity‐triggered muscle loss in humans.

Background Information about non-elite wheelchair basketball (WB) players across national competitive seasons are still missing. This study aimed at identifying which situational-related variables were associated with shooting effectiveness in non-elite WB players. Methods All the matches played by one WB team across one national competitive season were video-recorded and analysed; 333 shooting attempts from high-point players and several situational-related variables were considered. Results Pearson’s Chi-square test showed that increased shooting effectiveness under the following conditions: playing on home ground, during won matches, while taking shots with the wheelchair in motion, and when no opposing player raised their arm in defence. Results of the multivariable logistic regression analysis showed a statistically significant influence of match location (p-value = 0.001), shot-clock remaining (p-value = 0.015) and modality of press (p-value < 0.001). The highest attack effectiveness was achieved when teams played at home (odds ratio [OR] = 2.49), while the shooting effectiveness decreased when the shot occurred during the last seconds of the action (OR = 0.36), or the opponents defended with the arm raised (OR = 0.19). These results suggest that coaches should include exercises aimed at shooting under conditions of increased pressure in their programmes in order to create specific situations during the training sessions to prepare their high-point athletes for shots under specific match constraints.

Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1–/–). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01–treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.

Summary: Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Sepsis triggers sustained induction of autophagy, a key cellular degradative pathway, in skeletal muscles. However, the impact of enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM−KO), we investigated the functional importance of skeletal muscle autophagy in sepsis using the cecal ligation and puncture model. Atg7iSkM−KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting, hypoglycemia, higher ketone levels, and a decreased in survival as compared to mice with intact Atg7. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM−KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced muscle and metabolic dysfunctions and negatively impacts survival.

Background: Recent randomized trials (RCTs) in the field of robotic partial nephrectomy (PN) showed no significant differences in perioperative outcomes between the off- and on-clamp approaches. Objective: To compare the perioperative outcomes of on- versus off-clamp pure laparoscopic PN (LPN). Design, setting, and participants: A multi-institutional analysis of the on- versus off-clamp approach during LPN in the setting of an RCT (CLOCK II trial; ClinicalTrials.gov NCT02287987) was performed. Intervention: Off- versus on-clamp LPN. Outcome measurements and statistical analysis: Baseline patient and tumor variables, and peri- and postoperative data were collected. Randomized allocation with a 1:1 ratio was assigned. Surgical strategy for managing the renal pedicle was dictated by the study protocol. In the off-clamp arm, the renal artery had to remain unclamped for the duration of the whole procedure. Reporting the intention-to-treat analysis is the purpose of the study. Results and limitations: The study recruited 249 patients. Of them, 123 and 126 were randomized and allocated into the on- and off-clamp treatment groups, respectively. Treatment groups were comparable at baseline after randomization with respect to patients’ demographics, comorbidities, renal function, and tumor size and complexity. A univariable analysis found no differences in the perioperative outcomes between the groups, including median (interquartile range) estimated blood loss (150 [100–200] vs 150 [100–250] ml, p = 0.2), grade ≥2 complication rate as classified according to the Clavien-Dindo system (5.7% vs 4.8%, p = 0.6), and positive surgical margin rate (8.2% vs 3.5% for the on- vs off-clamp group, p = 0.1). No differences were found in terms of the 1st (81.3 [66.7–94.3] vs 85.3 [71.0–97.7] ml/min, p = 0.2) and 5th postoperative days estimated glomerular filtration rate (83.3 [70.5–93.7] vs 83.4 [68.6–139.3] ml/min, p = 0.2). A multivariable analysis found each +1 increase in RENAL score corresponded to an increase in the protection from the occurrence of complications (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.54–0.97, p = 0.034), while each +1 cm increase in tumor size corresponded to an increase in the risk of blood transfusion (OR 1.39, 95% CI 1.14–1.70, p = 0.001). Conclusions: In the setting of an RCT, no differences were found in the perioperative and early functional outcomes between on- and off-clamp LPN. Patient summary: In this study, we investigated, by means of a randomized trial, whether avoiding the clamping of renal artery during laparoscopic resection of renal mass is able to translate into benefits. We found no differences in terms of safety, efficacy, and renal function from the standard approach, which includes arterial clamping.

Abstract Introduction The role of glycemic control, both prior and during hospitalization, on mortality from COVID-19 in diabetic patients is debated. Furthermore, it is not clear whether hyperglycemia has a direct effect or requires inflammatory mechanisms. Objective To identify predictors of clinical outcomes (in-hospital mortality, length of hospitalization, respiratory failure, need for intensive care), considering hyperglycemia, inflammation markers and clinical history. Methods Retrospective observational study of 291 diabetic patients hospitalized with COVID-19 in the Spedali Civili di Brescia from February 1th 2020 to March 31th 2021, with also outpatient electronic records. Glucose, inflammatory parameters, creatinine were collected within 24 h after admission to the hospital. A causal mediation analysis allowed the estimation of the direct and indirect effects of hyperglycemia on mortality. Results Glucose at admission ≥ 165 mg/dL and reduced renal function were associated with an increased risk of in-hospital mortality and length of hospitalization (all p

ABSTRACT Objectives: To compare thulium laser enucleation of prostate (ThuLEP) versus laparoscopic trans-vesical simple prostatectomy (LSP) in the treatment of benign prostatic hyperplasia (BPH). Materials and Methods: Data of patients who underwent surgery for “large” BPH (>80mL) at three Institutions were collected and analyzed. Two institutions performed ThuLEP only; the third institution performed LSP only. Preoperative (indwelling catheter status, prostate volume (PVol), hemoglobin (Hb), Qmax, post-voiding residual volume (PVR), IPSS, QoL, IIEF-5) and perioperative data (operative time, enucleated adenoma, catheterization time, length of stay, Hb-drop, complications) were compared. Functional (Qmax, PVR, %ΔQmax) and patient-reported outcomes (IPSS, QoL, IIEF-5, %ΔIPSS, %ΔQoL) were compared at last follow-up. Results: 80 and 115 patients underwent LSP and ThuLEP, respectively. At baseline, median PVol was 130 versus 120mL, p

The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing. In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.

Abstract Background Evidence regarding clinically relevant effects of interventions aiming at reducing polypharmacy is weak, especially for the primary care setting. This study was initiated with the objective to achieve clinical benefits for older patients (aged 75+) by means of evidence-based reduction of polypharmacy (defined as ≥8 prescribed drugs) and inappropriate prescribing in general practice. Methods The cluster-randomised controlled trial involved general practitioners and patients in a northern-Italian region. The intervention consisted of a review of patient’s medication regimens by three experts who gave specific recommendations for drug discontinuation. Main outcome measures were non-elective hospital admissions or death within 24 months (composite primary endpoint). Secondary outcomes were drug numbers, hospital admissions, mortality, falls, fractures, quality of life, affective status, cognitive function. Results Twenty-two GPs/307 patients participated in the intervention group, 21 GPs/272 patients in the control group. One hundred twenty-five patients (40.7%) experienced the primary outcome in the intervention group, 87 patients (32.0%) in the control group. The adjusted rates of occurrence of the primary outcome did not differ significantly between the study groups (intention-to-treat analysis: adjusted odds ratio 1.46, 95%CI 0.99–2.18, p = 0.06; per-protocol analysis: adjusted OR 1.33, 95%CI 0.87–2.04, p = 0.2). Hospitalisations as single endpoint occurred more frequently in the intervention group according to the unadjusted analysis (OR 1.61, 95%CI 1.03–2.51, p = 0.04) but not in the adjusted analysis (OR 1.39, 95%CI 0.95–2.03, p = 0.09). Falls occurred less frequently in the intervention group (adjusted OR 0.55, 95%CI 0.31–0.98; p = 0.04). No significant differences were found regarding the other outcomes. Definitive discontinuation was obtained for 67 (16.0%) of 419 drugs rated as inappropriate. About 6% of the prescribed drugs were PIMs. Conclusions No conclusive effects were found regarding mortality and non-elective hospitalisations as composite respectively single endpoints. Falls were significantly reduced in the intervention group, although definitive discontinuation was achieved for only one out of six inappropriate drugs. These results indicate that (1) even a modest reduction of inappropriate medications may entail positive clinical effects, and that (2) focusing on evidence-based new drug prescriptions and prevention of polypharmacy may be more effective than deprescribing. Trial registration Current Controlled Trials (ID ISRCTN: 38449870), date: 11/09/2013.

Background This study assessed whether anthropometry, physical fitness and sport-specific sprint performance vary across the three groups of sitting volleyball (SV) athletes (athletes with a disability (VS1), athletes with a minimal disability (VS2) and able-bodied SV athletes (AB)) in order to explore the validity of the current system of classification. This study also investigated how the anthropometric and physical fitness characteristics of athletes relate to their sprint performance. Methods Thirty-five SV male athletes aged 37.4 ± 10.8 years and practicing SV at a national/international level volunteered for this study. Testing consisted in the evaluation of linear anthropometry, physical fitness (body composition by-means of dual-energy X-ray absorptiometry and upper-body strength) and sprint performance (5-meter sprint tests, agility test and speed and endurance test). Results Athletes in the three groups differed in fat mass percentage (%FM) which was higher in VS1 versus AB at the sub-total level (+9%), in the arms (+15%) and in the non-impaired leg (+8%) regions. Greater hand span, greater length of the impaired lower leg, lower %FM at both the sub-total and regional level and a higher level of strength in the upper body are all associated with better performances in the considered sprint tests (P

There is lack of information about bone mineralization at the lumbar spine and bilateral hips of athletes with unilateral lower limb amputation. The present study assessed for the first time the areal bone mineral density at the lumbar spine and at the hip of the able and impaired leg by means of Dual-Energy X-Ray Absorptiometry using a large sample (N = 40) of male athletes. Results showed that bone demineralization in athletes with unilateral lower limb amputation is found at the impaired hip but not at the lumbar spine and may therefore be site-specific. The extent of hip demineralization was influenced by the level of amputation, with about 80% of athletes with above knee amputation and 10% of athletes with below knee amputation showing areal bone mineral density below the expected range for age. Nevertheless, a reduced percentage of fat mass and a lower fat-to-lean mass ratio in the residual impaired leg as well as a greater amount of weekly training was positively associated with bone mineralization at the impaired hip (partial correlation coefficients = 0.377–0.525, p = 0.040–0.003). Results showed that participation in adapted sport has a positive effect on bone health in athletes with unilateral lower limb amputation but is not sufficient to maintain adequate levels of bone mineralization at the impaired hip in athletes with above-knee amputation. Accordingly, physical conditioners should consider implementing sporting programs, according to the severity of the impairment, aimed at improving bone mineralization at the impaired hip and improve body composition in the residual impaired leg.

Abstract Background A precondition for developing strategies to reduce polypharmacy and its well-known harmful consequences is to study its epidemiology and associated factors. The objective of this study was to analyse the prevalence of polypharmacy (defined as ≥8 prescribed drugs), of potentially inappropriate medications (PIMs) and major drug-drug interactions (DDIs) among community-dwelling general practice patients aged ≥75 years and to identify characteristics being associated with polypharmacy. Methods This cross-sectional study is derived from baseline data (patients’ demographic/biometric characteristics, diagnoses, medication-related data, cognitive/affective status, quality of life) of a northern-Italian cluster-RCT. PIMs and DDIs were assessed using the 2012 Beers criteria and the Lexi-Interact® database. Data were analysed using descriptive methods, Wilcoxon rank-sum tests, Fisher’s exact tests and Spearman correlations. Results Of the eligible patients aged 75+, 13.4% were on therapy with ≥8 drugs. Forty-three general practitioners and 579 patients participated in the study. Forty five point nine percent of patients were treated with ≥1 Beers-listed drugs. The most frequent PIMs were benzodiazepines/hypnotics (19.7% of patients) and NSAIDs (6.6%). Sixty seven point five percent of patients were exposed to ≥1 major DDI, 35.2% to ≥2 major DDIs. Antithrombotic/anticoagulant medications (30.4%) and antidepressants/antipsychotics (23.1%) were the most frequently interacting drugs. Polypharmacy was significantly associated with a higher number of major DDIs (Spearman’s rho 0.33, p

Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels’ upregulation, neuromuscular junction and axonal damage, neurotrophins’ receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.

Olfactory areas in mammalian brains are linked to centers that modulate behavior. During aging, sensitivity to odors decreases and structural changes are described in olfactory areas. We explored, in two groups of male mice (young and elderly, 6 and 19 months old, respectively), the link between the changes in olfactory bulb structure, detected with magnetic resonance imaging, and behavioral changes in a battery of tests on motor, olfactory, cognitive performance, and emotional reactivity. The behavioral pattern of elderly mice appears less anxious, being less scared by new situations. Additionally, the olfactory bulb of young and elderly mice differed in two variables derived from magnetic resonance imaging (fractional anisotropy and T2 maps). A random forest approach allowed to select the variables most predictive of the differences between young and elderly mice, and correlations were found between three behavioral variables indicative of anxious behavior and the two magnetic resonance variables mentioned above. These data suggest that in the living mouse, it is possible to describe co-occurring age-related behavioral and structural changes in the olfactory bulb. These data serve as a basis for studies on normal and pathological aging in the mouse, but also open new opportunities for in vivo human aging studies.

Loss of muscle mass is associated with ageing and with a number of diseases such as cancer. Here, the authors review the signaling pathways that modulate protein synthesis and degradation and gain or loss of muscle mass, and discuss therapeutic implications and future directions for the field.

Abstract Background Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined. Methods Inducible, muscle‐specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force. Results We found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle‐specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3–8% of NCAM‐positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat‐beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM‐positive fibres in Raptor k.o. muscles. Conclusions Our study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well‐established activation of mTORC1 in skeletal muscle during and after exercise.

Ageing is associated with muscle atrophy, which negatively impacts quality of life. Here the authors show that expression of sestrins decreases during inactivity and that their overexpression prevents atrophy in mice via modulation of autophagy and protein degradation.

Background The impact of the type and the severity of disability on whole-body and regional body composition (BC), and bone mineral density (BMD) must be considered for dietary advice in athletes with a physical impairment (PI). This study aimed to investigate the impact of the type and the severity of disability on BC, the pattern of distribution of fat mass at the regional level, and BMD in athletes with a PI. Methods Forty-two male athletes with spinal cord injury (SCI, n = 24; age = 40.04 ± 9.95 years, Body Mass Index [BMI] = 23.07 ± 4.01 kg/m2) or unilateral lower limb amputation (AMP, n = 18; age = 34.39 ± 9.19 years, BMI = 22.81 ± 2.63 kg/m2) underwent a Dual-Energy X-Ray Absorptiometry scan. Each athlete with a PI was matched by age with an able-bodied athlete (AB, n = 42; age = 37.81 ± 10.31 years, BMI = 23.94 ± 1.8 kg/m2). Results One-Way Analysis of Variance showed significant differences between the SCI, AMP and AB groups for percentage fat mass (%FM) (P < 0.001, eta squared = 0.440). Post-hoc analysis with Bonferroni’s correction showed that athletes with SCI had significantly higher %FM vs. the AMP and AB groups (25.45 ± 5.99%, 21.45 ± 4.21% and 16.69 ± 2.56%, respectively; P = 0.008 vs. AMP and P < 0.001 vs. AB). The %FM was also significantly higher in the AMP vs. the AB group (P < 0.001). Whole-body BMD was negatively affected in SCI athletes, with about half of them showing osteopenia or osteoporosis. In fact, the mean BMD and T-score values in the SCI group (1.07 ± 0.09 g/cm2 and −1.25 ± 0.85, respectively) were significantly lower in comparison with the AB group (P = 0.001 for both) as well as the AMP group (P = 0.008 for both). The type of disability affected BC and BMD in the trunk, android, gynoid and leg regions in SCI athletes and the impaired leg only in AMP athletes. Conclusions In conclusion, the type of disability and, partly, the severity of PI impact on BC and BMD in athletes with a PI. Nutritionists, sports medicine doctors, clinicians, coaches and physical conditioners should consider athletes with SCI or AMP separately. Athletes with a PI would benefit from specific nutrition and training programs taking into account the type of their disability.

Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.

Abstract Background Stimulation of β2‐adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive. Methods Fed wild type (WT), 2‐day fasted WT, muscle‐specific insulin (INS) receptor (IR) knockout (M‐IR−/−), and MKR mice were studied with regard to acute effects of the β2‐agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 μg kg−1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 μg kg−1 day−1) for 30 days. Results In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3‐II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4‐fold to 25‐fold, P ≤ 0.05) and the phosphorylation of Akt (4.4‐fold to 6.5‐fold, P ≤ 0.05) and ERK1/2 (50% to two‐fold, P ≤ 0.05). This led to the suppression (40–70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4‐fold to 35‐fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M‐IR−/− and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of β2‐adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy‐related genes (30–40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR‐induced slow‐to‐fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleated fibers. Conclusions NS/IGF1 signalling is necessary for the anti‐proteolytic and hypertrophic effects of in vivo β2‐adrenergic stimulation and appears to mediate FOR‐induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR.

Abstract Background Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. Methods By mean of in vivo Plin2 down‐regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. Results We found that Plin2 down‐regulation was sufficient to induce a 30% increase of myofiber cross‐sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. Conclusions Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

To date there is no anthropometric equation specific to athletes with unilateral lower limb amputation to estimate the percentage of fat mass (%FM). This study investigated the accuracy of a set of anthropometric equations validated on able-bodied populations to predict the %FM assessed by-means of dual-energy x-ray absorptiometry (DXA) in athletes with unilateral lower limb amputation. Furthermore, a predictive anthropometric equation specific to athletes with unilateral lower limb amputation was developed from skinfold thickness measurements using DXA as the reference method for the estimation of the %FM. Twenty-nine white male athletes with unilateral lower limb amputation underwent a DXA scan and an anthropometric assessment on the same day. The %FM, calculated through several existing anthropometric equations validated upon able-bodied populations, was compared with the DXA-measured %FM (%FM_DXA). Accuracy and agreement between the two methods was computed with two-tailed paired-sample t-test, concordance correlation coefficient, reduced major axis regression and Bland-Altman analysis. A stepwise multiple regression analysis with the %FM_DXA as the dependent variable and age and nine skinfold thicknesses as potential predictors was carried out and validated using a repeated 10-fold cross-validation. A linear regression analysis with the sum of nine skinfolds as the independent variable was also carried out and validated using a repeated 10-fold cross-validation. The results showed that the anthropometric equations validated on able-bodied populations are inaccurate in the estimation of %FM_DXA with an average bias ranging from 0.51 to −13.70%. Proportional bias was also found revealing that most of the anthropometric equations considered, tended to underestimate/overestimate the %FM_DXA as body fat increased. Regression analysis produced two statistically significant models (P < 0.001 for both) which were able to predict more than 93% of total variance of %FM_DXA from the values of four skinfold measurements (i.e., thigh, abdominal, subscapular and axillary skinfold measurements) or from the sum of 9 skinfolds. Repeated cross-validation analysis highlighted a good predictive performance of the proposed equations. The predictive equations proposed in this study represent a useful tool for clinicians, nutritionists, and physical conditioners to evaluate the physical and nutritional status of athletes with unilateral lower limb amputation directly in the field.

Purpose The determinants of physical fitness in children have been given limited attention. In particular, the relative role of chronological age, sex, anthropometry, and body composition in physical fitness of children has been barely investigated. This cross-sectional study investigated determinants of physical fitness using a set of predictive variables including, in addition to chronological age and sex, a large panel of anthropometric measurements as well as body composition. The study was carried out in a convenience sample of children aged 6–12 participating in a summer camp. Methods One-hundred-ninety-three children (128 males) fulfilled all requirements and entered analysis. Health-related physical fitness components (speed, muscular power and balance) were explored by means of field tests, namely the 30-m dash test for running speed, the standing long jump and the seated chest pass test for lower limbs and upper body muscular power, respectively, and the flamingo balance test for static balance. Determinants of physical fitness were investigated by regression analysis using chronological age, sex, anthropometry, and body composition in a hierarchical approach. To minimize the expected effect of collinearity in predictor variables, an original statistical approach using Random Forests analysis was adopted. Results Age predicted 45.2%, 43.6%, 35.6% and 25.6%; and sex 9.5%, 10.7%, 6.3% and 2.0% of variance in the 30-m dash, seated chest pass, standing long jump, and flamingo balance test, respectively. Anthropometry and body composition explained a limited or no percentage of variance. The adjusted R2 (root mean square error) was 0.61 (0.31 s), 0.45 (0.32 m), 0.58 (0.15 m) and 0.41 (0.75 logs) for the 30-m dash, seated chest pass, standing long jump, and flamingo balance test, respectively making these models useful when physical fitness tests are not feasible. Conclusions We highlighted the respective role of chronological age, sex, anthropometry, and body composition in physical fitness of children in the wide age range 6–12 years. Data confirm and expand on previous literature by showing with a strictly conservative statistical approach that chronological age is a main determinant of physical fitness of both boys and girls, sex playing a limited role. The role of anthropometry was even less important, and no role was found for body composition. These findings should be considered when planning/implementing motor development or physical education programs.

Several research studies were focused to understand how grapevine cultivars respond to environment; nevertheless, the biological mechanisms tuning this phenomenon need to be further deepened. Particularly, the molecular processes underlying the interplay between clones of the same cultivar and environment were poorly investigated. To address this issue, we analyzed the transcriptome of berries from three "Nebbiolo" clones grown in different vineyards, during two ripening seasons. RNA-sequencing data were implemented with analyses of candidate genes, secondary metabolites, and agronomical parameters. This multidisciplinary approach helped to dissect the complexity of clone × environment interactions, by identifying the molecular responses controlled by genotype, vineyard, phenological phase, or a combination of these factors. Transcripts associated to sugar signalling, anthocyanin biosynthesis, and transport were differently modulated among clones, according to changes in berry agronomical features. Conversely, genes involved in defense response, such as stilbene synthase genes, were significantly affected by vineyard, consistently with stilbenoid accumulation. Thus, besides at the cultivar level, clone-specific molecular responses also contribute to shape the agronomic features of grapes in different environments. This reveals a further level of complexity in the regulation of genotype × environment interactions that has to be considered for orienting viticultural practices aimed at enhancing the quality of grape productions.

Summary: Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c−/− muscles. In addition, we demonstrate that METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude that the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions. : Wiederstein et al. describe the skeletal muscle methyltransferase Mettl21c. They found that ablation of Mettl21c in mice results in muscle weakness and disturbance of the protein degradation machinery. Those changes are hallmarks of multisystem proteinopathies. They demonstrate that Mettl21c modulates p97 activity, which is frequently mutated in human patients with muscle weakness. Keywords: methyltransferases, skeletal muscle, p97, atrophy, autophagy

Abstract Background Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer. Methods This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result. Results Mean pathological tumor size was 10.5 mm (±4.3, range 3–18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107–213; range:56–325) with a median PTV isodose prescription of 86.0% (IQR 85.0–88.5; range:82–94). The median PTV was 88.1 cm3 (IQR 63.8–108.6; range:32.3–238.8). The median breast V100 and V50 was 0.6 (IQR 0.1–1.5; range:0–13) and 18.6 (IQR 13.1–21.7; range:7.5–37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7–27.6; range 22.3–29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients’ evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer. Conclusions These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results. Trial registration The present study is registered at Clinicaltrial.gov (NCT02896322). Retrospectively egistered August 4, 2016.

Cachexia is a metabolic syndrome leading to muscle and adipose tissue loss in majority of cancer patients. Here the authors show that, in a mouse model, BET inhibitor JQ1 counteracts muscle and adipose tissue wasting tempering cachexia and prolonging survival through a mechanism unrelated to tumour growth.

Background: The potassium channel encoded by the ether-a-gogo-related gene 1A (erg1a) has been detected in the atrophying skeletal muscle of mice experiencing either muscle disuse or cancer cachexia and further evidenced to contribute to muscle deterioration by enhancing ubiquitin proteolysis; however, to our knowledge, ERG1A has not been reported in human skeletal muscle. Methods and Results: Here, using immunohistochemistry, we detect ERG1A immunofluorescence in human Rectus abdominis skeletal muscle sarcolemma. Further, using single point brightness data, we report the detection of ERG1A immunofluorescence at low levels in the Rectus abdominis muscle sarcolemma of young adult humans and show that it trends toward greater levels (10.6%) in healthy aged adults. Interestingly, we detect ERG1A immunofluorescence at a statistically greater level (53.6%; p < 0.05) in the skeletal muscle of older cancer patients than in age-matched healthy adults. Importantly, using immunoblot, we reveal that lower mass ERG1A protein is 61.5% (p < 0.05) more abundant in the skeletal muscle of cachectic older adults than in healthy age-matched controls. Additionally, we report that the ERG1A protein is detected in a cultured human rhabdomyosarcoma line that may be a good in vitro model for the study of ERG1A in muscle. Conclusions: The data demonstrate that ERG1A is detected more abundantly in the atrophied skeletal muscle of cancer patients, suggesting it may be related to muscle loss in humans as it has been shown to be in mice experiencing muscle atrophy as a result of malignant tumors.

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1–UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.

Fibroblast growth factor 21 (FGF21) is a hormone that regulates important metabolic pathways. FGF21 is expressed in several metabolically active organs and interacts with different tissues. The FGF21 function is complicated and well debated due to its different sites of production and actions. Striated muscles are plastic tissues that undergo adaptive changes within their structural and functional properties in order to meet their different stresses, recently, they have been found to be an important source of FGF21. The FGF21 expression and secretion from skeletal muscles happen in both mouse and in humans during their different physiological and pathological conditions, including exercise and mitochondrial dysfunction. In this review, we will discuss the recent findings that identify FG21 as beneficial and/or detrimental cytokine interacting as an autocrine or endocrine in order to modulate cellular function, metabolism, and senescence.

Summary: Skeletal muscle is composed of different myofiber types that preferentially use glucose or lipids for ATP production. How fuel preference is regulated in these post-mitotic cells is largely unknown, making this issue a key question in the fields of muscle and whole-body metabolism. Here, we show that microRNAs (miRNAs) play a role in defining myofiber metabolic profiles. mRNA and miRNA signatures of all myofiber types obtained at the single-cell level unveiled fiber-specific regulatory networks and identified two master miRNAs that coordinately control myofiber fuel preference and mitochondrial morphology. Our work provides a complete and integrated mouse myofiber type-specific catalog of gene and miRNA expression and establishes miR-27a-3p and miR-142-3p as regulators of lipid use in skeletal muscle. : Chemello et al. characterize coding mRNAs and non-coding microRNAs expressed by myofibers of hindlimb mouse muscles, identifying complex interactions between these molecules that modulate mitochondrial functions and muscle metabolism. They demonstrate that specific short non-coding RNAs influence the contractile fiber composition of skeletal muscles by modulating muscle metabolism. Keywords: single myofiber, skeletal muscle metabolism, mitochondria, miRNAs, lipids

Human aging is characterized by dramatic changes in body mass composition that include a general increase of the total fat mass. Within the fat mass, a change in the proportions of adipose tissues also occurs with aging, affecting body metabolism, and playing a central role in many chronic diseases, including insulin resistance, obesity, cardiovascular diseases, and type II diabetes. In mammals, fat accumulates as white (WAT) and brown (BAT) adipose tissue, which differ both in morphology and function. While WAT is involved in lipid storage and immuno-endocrine responses, BAT is aimed at generating heat. With advancing age BAT declines, while WAT increases reaching the maximum peak by early old age and changes its distribution toward a higher proportion of visceral WAT. However, lipids tend to accumulate also within lipid droplets (LDs) in non-adipose tissues, including muscle, liver, and heart. The excess of such ectopic lipid deposition and the alteration of LD homeostasis contribute to the pathogenesis of the above-mentioned age-related diseases. It is not clear why age-associated tissue remodeling seems to lean toward lipid deposition as a “default program.” However, it can be noted that such remodeling is not inevitably detrimental. In fact, such a programmed redistribution of fat throughout life could be considered physiological and even protective, in particular at extreme old age. In this regard, it has to be considered that an excessive decrease of subcutaneous peripheral fat is associated with a pro-inflammatory status, and a decrease of LD is associated with lipotoxicity leading to an increased risk of insulin resistance, type II diabetes and cardiovascular diseases. At variance, a balanced rate of fat content and distribution has beneficial effects for health and metabolic homeostasis, positively affecting longevity. In this review, we will summarize the present knowledge on the mechanisms of the age-related changes in lipid distribution and we will discuss how fat mass negatively or positively impacts on human health and longevity.

This study tested the effect of two block setting conditions i.e., the usual block setting [US] and an anthropometry-driven block setting [AS] on the kinematic and kinetic parameters of the sprint start. Furthermore, we verified whether this effect is influenced by the relative lengths of the sprinter's trunk and lower limbs i.e., the Cormic Index by subdividing sprinters into brachycormic, metricormic and macrocormic groups. Forty-two sprinters performed 6 maximal-effort 10 m sprints using the US and AS conditions. Dynamometric starting blocks measured forces generated by the sprinters. The times at 5 m and 10 m in the sprint trials were measured with photocells. Results showed that the anteroposterior block distances were significantly different between the two conditions (P

Background Apolipoprotein CIII (apo CIII) is a crucial player in triglyceride‐rich lipoprotein metabolism, but may also act pleiotropically, provoking inflammatory responses and stimulating coagulation. Elevated apoCIII plasma levels have been associated with increased activity of coagulation factors. Since these features of prothrombotic diathesis are linked with venous thromboembolism (VTE), we hypothesized that apo CIII plays a role in VTE. Methods and Results We recorded nonfatal VTE events in 1020 patients (age 63.3±11.4 years; 29.1% women) with or without coronary artery disease (79.1% with coronary artery disease and 20.9% without coronary artery disease) during a long follow‐up. Complete plasma lipid and apolipoproteins were available for all patients. Forty‐five patients (4.4%) experienced nonfatal VTE events during a median follow‐up period of 144 months. Apo CIII plasma concentration at enrollment was higher in patients with VTE compared with patients without VTE (12.2 [95% CI, 11.10–13.5] mg/dL vs 10.6 [95% CI, 10.4–10.9] mg/dL, respectively; P=0.011). Patients with apo CIII levels above the median value (10.6 mg/dL) exhibited an increased risk of VTE (incidence rate, 6.0 [95% CI, 4.0–8.0] vs 1.8 [95% CI, 0.7–2.9] VTE events/1000 person‐years; unadjusted hazard ratio [HR], 3.42 [95% CI, 1.73–6.75]; P

The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25−37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment.

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.

Androgens are primarily involved in muscle growth, whilst disease-driven muscle wasting is frequently associated with hypogonadism. The Leydig cells of the testes also produce the peptide-hormone Insulin-like peptide 3 (INSL3). INSL3 displays anabolic activity on bone, a target tissue of androgens, and its plasma concentrations are diminished in male hypogonadism. Here we tested the role of INSL3 on muscle mass regulation, in physiological and pathological conditions. Studies on C2C12 cell line showed that INSL3, acting on his specific receptor RXFP2, promotes skeletal muscle protein synthesis through the Akt/mTOR/S6 pathway. Next, studies on Rxfp2−/− mice showed that INSL3 is required to prevent excessive muscle loss after denervation. Mechanistically, denervated Rxfp2−/− mice lacked the compensatory activation of the Akt/mTOR/S6 pathway and showed an abnormal ubiquitin-proteasome system activation. Lack of INSL3 activity resulted also in reduced contractile force. These findings underlie a role of INSL3/RXFP2 in protein turnover, contributing to muscle wasting in male hypogonadism.