Sex differences in the involvement of skeletal and cardiac muscles in myopathic Ano5-/- mice.

Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by recessive mutations in the Anoctamin-5 gene (ANO5, TMEM16E). Although ANO5 myopathy is not X-chromosome linked, we performed a meta-analysis of the research literature and found that three-quarters of LGMD-R12 patients are males. Females are less likely to present with moderate to severe skeletal muscle and/or cardiac pathology. Because these sex differences could be explained in several ways, we compared males and females in a mouse model of LGMD-R12. This model recapitulates the sex differences in human LGMD-R12. Only male Ano5-/- mice had elevated serum creatine kinase after exercise and exhibited defective membrane repair after laser injury. In contrast, by these measures, female Ano5-/- mice were indistinguishable from wild type. Despite these differences, both male and female Ano5-/- mice exhibited exercise intolerance. While exercise intolerance of male mice can be explained by skeletal muscle dysfunction, echocardiography revealed that Ano5-/- female mice had features of cardiomyopathy that may be responsible for their exercise intolerance. These findings heighten concerns that mutations of ANO5 in humans may be linked to cardiac disease.

Ultrasonic Elastography of the Rectus Femoris, a Potential Tool to Predict Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease

Purpose: Skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. Abnormal muscle quantity of the lower limbs is a manifestation of skeletal muscle dysfunction in patients with COPD. Shear wave ultrasound elastography (SWE) is a novel and possible tool to evaluate qualitative muscle parameters. This study explores the feasibility of SWE to measure the stiffness of the rectus femoris and evaluates its value in predicting sarcopenia in patients with COPD.Methods: Ultrasound examination of the rectus femoris was performed to determine the mean elasticity index (SWEmean), cross-sectional area (RFcsa), and thickness (RFthick) using grayscale ultrasonography (US) and SWE in 53 patients with COPD and 23 age-matched non-COPD healthy controls. The serum levels of circulating biomarkers (GDF15, resistin, and TNF-α) were measured using ELISA. The definition of sarcopenia followed the guidelines from the Asian Working Group for Sarcopenia. Receiver operating characteristic (ROC) curve analysis of the SWEmean, RFthick, and RFcsa was used to evaluate their predictive ability for sarcopenia.Results: The intraobserver and interobserver repeatability of SWE performance was excellent (all correlation coefficients > 0.95; p < 0.05). The SWEmean of the rectus femoris in patients with COPD (8.98 ± 3.12 kPa) was decreased compared with that in healthy controls (17.00 ± 5.14 kPa) and decreased with advanced global initiative for chronic obstructive lung disease (GOLD) stage. Furthermore, SWEmean was found to be independent of sex, height, and body mass, and a lower SWEmean in patients with COPD was positively associated with reduced pulmonary function, worse physical function, poor exercise tolerance, decreased muscle strength, and worse dyspnea index score. The correlation between physical function [five-repetition sit-to-stand test (5STST)], muscle function, and SWEmean was higher than those of RFthick and RFcsa. In addition, SWEmean was negatively correlated with serum GDF15 levels (r = −0.472, p < 0.001), serum resistin levels (r = −0.291, p = 0.035), and serum TNF-α levels (r = −0.433, p = 0.001). Finally, the predictive power of SWEmean [area under the curve (AUC): 0.863] in the diagnosis of sarcopenia was higher than that of RFthick (AUC: 0.802) and RFcsa (AUC: 0.816).Conclusion: Compared with grayscale US, SWE was not affected by the patient’s height, weight, or BMI and better represented skeletal muscle function and physical function. Furthermore, SWE is a promising potential tool to predict sarcopenia in patients with COPD.

PGC1α protects against cisplatin-induced skeletal muscle dysfunction

Background and Hypothesis: We and others have shown that chemotherapy promotes skeletal muscle wasting and weakness (i.e., cachexia) by disrupting mitochondrial homeostasis and causing oxidative stress. Peroxisome proliferative-activated receptor gamma coactivator 1-alpha (PGC1α) is a pivotal regulator of mitochondrial biogenesis and is involved in reducing oxidative damage in skeletal muscle. Hence, in the present study we investigated whether overexpression of skeletal muscle PGC1α (mPGC1α) was sufficient to preserve skeletal muscle mass and function in young and old mice treated with cisplatin. Experimental Design or Project Methods: Young (2-month; n = 5) and old (18-month; n = 5-8) male wild type (WT) or mPGC1α transgenic mice were treated with cisplatin (2.5mg/kg), while age-matched WT mice received vehicle for 2 weeks. Animals were assessed for muscle force and motor unit number estimation (MUNE). Skeletal muscles were weighed and processed for molecular analyses, including assessment of mitochondrial protein content. Results: Young WT mice exposed to cisplatin showed evidence of cachexia, as indicated by reduced gastrocnemius size (-16%), plantarflexion force (-8%) and MUNE (-56%), whereas mPGC1α mice were only partially protected. Interestingly, despite exacerbated cachexia in aged WT mice treated with chemotherapy, as demonstrated by markedly decreased gastrocnemius size (-22%), plantarflexion force (-18%) and MUNE (-80%) compared to untreated WT, muscle mass, strength and innervation were fully preserved in age-matched mPGC1α mice. Follow-up molecular analyses revealed that WT animals exposed to chemotherapy present loss of muscle mitochondrial proteins PGC1α, OPA1 and CytochromeC, whereas their levels in mPGC1α mice were robustly increased. Conclusion and Potential Impact: Altogether, our data suggest that PGC1α plays a pivotal role in preserving skeletal muscle mass and function, usually impaired by anticancer treatments. These findings enforce developing mitochondria-targeting therapeutics to combat the negative consequences that chemotherapy has on skeletal muscle.

Exercise-Based Pulmonary Rehabilitation for Interstitial Lung Diseases: A Review of Components, Prescription, Efficacy, and Safety

Interstitial lung diseases (ILDs) comprise a heterogeneous group of disorders (such as idiopathic pulmonary fibrosis, sarcoidosis, asbestosis, and pneumonitis) characterized by lung parenchymal impairment, inflammation, and fibrosis. The shortness of breath (i.e., dyspnea) is a hallmark and disabling symptom of ILDs. Patients with ILDs may also exhibit skeletal muscle dysfunction, oxygen desaturation, abnormal respiratory patterns, pulmonary hypertension, and decreased cardiac function, contributing to exercise intolerance and limitation of day-to-day activities. Pulmonary rehabilitation (PR) including physical exercise is an evidence-based approach to benefit functional capacity, dyspnea, and quality of life in ILD patients. However, despite recent advances and similarities with other lung diseases, the field of PR for patients with ILD requires further evidence. This mini-review aims to explore the exercise-based PR delivered around the world and evidence supporting prescription modes, considering type, intensity, and frequency components, as well as efficacy and safety of exercise training in ILDs. This review will be able to strengthen the rationale for exercise training recommendations as a core component of the PR for ILD patients.

Muscle-Bone Crosstalk in Chronic Obstructive Pulmonary Disease

Sarcopenia and osteoporosis are common musculoskeletal comorbidities of chronic obstructive pulmonary disease (COPD) that seriously affect the quality of life and prognosis of the patient. In addition to spatially mechanical interactions, muscle and bone can also serve as endocrine organs by producing myokines and osteokines to regulate muscle and bone functions, respectively. As positive and negative regulators of skeletal muscles, the myokines irisin and myostatin not only promote/inhibit the differentiation and growth of skeletal muscles, but also regulate bone metabolism. Both irisin and myostatin have been shown to be dysregulated and associated with exercise and skeletal muscle dysfunction in COPD. During exercise, skeletal muscles produce a large amount of IL-6 which acts as a myokine, exerting at least two different conflicting functions depending on physiological or pathological conditions. Remarkably, IL-6 is highly expressed in COPD, and considered to be a biomarker of systemic inflammation, which is associated with both sarcopenia and bone loss. For osteokines, receptor activator of nuclear factor kappa-B ligand (RANKL), a classical regulator of bone metabolism, was recently found to play a critical role in skeletal muscle atrophy induced by chronic cigarette smoke (CS) exposure. In this focused review, we described evidence for myokines and osteokines in the pathogenesis of skeletal muscle dysfunction/sarcopenia and osteoporosis in COPD, and proposed muscle-bone crosstalk as an important mechanism underlying the coexistence of muscle and bone diseases in COPD.

Mutant huntingtin crosses the neuromuscular junction and causes transmission-selective pathological alterations in huntingtin expressing myotubes

Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntingtons disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell- (hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhances transmission. Also, our data reveals that transmission happens prior to aggregate formation and that aggregation occurs progressively with continuous transmission across weeks at the myotube surface. Furthermore, we provide evidence that mHTTEx1 derived from MNs causes defragmentation of mitochondria and exacerbates nuclear aggregation, the latter in the presence of myotube autonomous mHTTEx1. Finally, we find that mHTTEx1 transmission results in decreased myotube contractions, in contrast myotube autonomous expression causes a hyperexcitable-like phenotype. Altogether, our data suggests that mHTTEx1 neuromuscular transmission contributes to skeletal muscle dysfunction in HD, via continuous transmission of the toxic protein already at early preclinical stages of HD and thereby contributes to an increasing accumulation of toxic protein in skeletal muscle, eventually leading to a highly-selective phenotype resulting in a decline of skeletal muscle function. Since multiple studies support a role of synaptic transmission of diverse misfolded proteins, including tau in Alzheimers, alpha-synuclein in Parkinsons, mHTT in HD, tdp-43 in Amyotrophic lateral sclerosis and frontotemporal lobar dementia, in the central nervous system, this process likely represents a common synaptic-linked pathobiological pathway for most neurodegenerative protein misfolding diseases.

Correlation of Reduced Endurance Capacity of Neck Flexor and Extensor in Cigarette Smokers of College Going Students

Background: Muscle endurance is the ability of muscle to contract repeatedly against a load (resistance), generated and sustain tension and resist fatigue over an extended period of time. Smoking causes variety of health diseases and it also affects skeletal muscle dysfunction as well. Cigarette smoke constituents and systemic inflammatory mediators enhance proteolysis and inhibit protein synthesis, leading to loss of muscle mass. Objectives: To find out the correlation between the neck flexor endurance capacity and neck extensor endurance capacity with 1-5 years of smoking history. Methods: Data collection was done from college of physiotherapy and college of nursing using convenient sampling. 60 Male subjects were included in study between the age group of 20-30 years with 1-5 years of smoking history. The score of neck flexor endurance capacity and neck extensor endurance capacity using neck flexor endurance test and neck extensor endurance test, and the data were analyzed. Result: The result of study showed a statistical significance in the neck flexor and extensor endurance capacity (p=<0.001) (r=-0.59 for NFEC, -0.54 for NEEC) using neck flexor endurance capacity test and neck extensor endurance capacity test in subjects with 1-5 years of smoking history. Conclusion: The study concludes that there is reduced endurance capacity of neck flexor and neck extensor muscles in smokers with 1-5 years of smoking history. Key words: Cigarette smoking, muscle strength, neck flexor and extensor endurance test, 1-5 years smoking history.