Skeletal Muscle Disorders Research Articles

Activation of Transposable Elements in Human Skeletal Muscle Fibers upon Statin Treatment.

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.

Effect of Core Stability Exercises in Reducing Complaints of Low Back Pain on the Pembatik Across the City of Jambi

Batik craftsmen tend to be in a long sitting position, followed by a batik position that is not ergonomic, the way they work, all of which still use the manual method, of course, will cause a lot of complaints or skeletal muscle disorders. So far, batik makers usually treat low back pain by resting without any treatment. There is a need for physiotherapy modalities that can be applied to batik, such as core stability. To analyze the effect of core stability exercise in lowering the lower back in the batik group Seberang Jambi City. This type of research is a quasi-experimental research with pre-test and post-test with control group design. The research sample amounted to 20 respondents. The measuring instrument uses the Visual Analog Scale (VAS). The data analysis technique used Paired Sample T-Test and Independent Sample T-Test. There was a significant effect on the core stability exercise group in lowering the lower back. There is a difference in the effect of core stability exercises in lowering the lower back on batik at the Kajang Lako Seberang Cooperative, Jambi City.

EFFECTS OF FLAVANOL (+)-EPICATECHIN ON SKELETAL MUSCLE OF AGED RATS

Abstract Sarcopenia is a progressive and generalized age-related skeletal muscle (SkM) disorder characterized by the accelerated loss of muscle mass (atrophy) and function. SkM atrophy is associated with increased incidence of falls, functional decline, frailty and mortality. In its early stage, SkM atrophy is associated with oxidative stress, increased pro-inflammatory cytokine levels and proteasome-mediated protein degradation. These processes also link to the activation of atrophy associated factors and signaling pathways which lack any approved, targeted pharmacotherapy. We have characterized the capacity of flavanols specifically, epicatechin to favorably modulate SkM mass and function in animal models of SkM disease and in proof of concept studies in humans including muscular dystrophies. In this study we wished to evaluate the capacity of this flavanol to ameliorate aging associated sarcopenia. Using 24-month-old male rats a 4 week oral administration of the flavanol (+)-epicatechin (1mg/kg/day) was implemented while control rats only received vehicle (water). SkM strength (grip) and endurance (treadmill walk), muscle size, (muscle mass, cross sectional area of fibers), ubiquitin-proteasome atrophic pathway (including myostatin, Murf1 and Atrogin1 by Western blots) and markers of oxidative stress and inflammation in gastrocnemius were quantified. We also analyzed a relevant protein synthesis pathway (IGF/AKT/mTOR). The use of (+)-epicatechin in aged rats led to significant changes as follows: 1) improved SkM mass and function, 2) downregulation of atrophic pathway, 3) reduced levels of oxidative stress and proinflammatory cytokines and, 4) upregulation of protein synthesis pathway. Given its safety and tolerance profile this agent warrant its rigorous investigation in clinical trials.

A systematic review and meta-analysis of the prevalence and correlation of mild cognitive impairment in sarcopenia.

Sarcopenia is a progressive skeletal muscle disorder involving the loss of muscle mass and function, associated with an increased risk of disability and frailty. Though its prevalence in dementia has been studied, its occurrence in mild cognitive impairment (MCI) has not been well established. As MCI is often a prelude to dementia, our study aims to investigate the prevalence of MCI among individuals with sarcopenia and to also ascertain whether sarcopenia is independently associated with MCI. The Cochrane Library, PubMed, Ovid, Embase and Web of Science were systematically searched for articles on MCI and/or sarcopenia published from inception to 1 February 2022. We reviewed the available literature on the number of individuals with MCI and/or sarcopenia and calculated odds ratios (ORs) of sarcopenia in MCI and MCI in sarcopenia, respectively. Statistical analyses were performed using the meta package in Stata, Version 12.0. A total of 13 studies and 27428 patients were included in our analysis. The pooled prevalence of MCI in participants with sarcopenia was 20.5% (95% confidence interval [CI]: 0.140-0.269) in a total sample of 2923 cases with a high level of heterogeneity (P<0.001; I2 =95.4%). The overall prevalence of sarcopenia with MCI was 9.1% (95% CI: 0.047-0.134, P<0.001; I2 =93.0%). For overall ORs, there were 23364 subjects with a mean age of 73years; the overall adjusted OR between MCI and sarcopenia was 1.46 (95% CI: 1.31-1.62). Slight heterogeneity in both adjusted ORs (P=0.46; I2 =0%) was noted across the studies. The prevalence of MCI is relatively high in patients with sarcopenia, and sarcopenia may be a risk factor for MCI.

Preservation of shortening velocity and power output in single muscle fibres from patients with idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders of skeletal muscle causing weakness and disability. Utilizing single fibre contractility studies, we have previously shown that contractility is affected in muscle fibres from individuals with IIMs. For the current study, we hypothesized that a compensatory increase in shortening velocity occurs in muscle fibres from individuals with IIMs in an effort to maintain power output. We performed in vitro single fibre contractility studies to assess force-velocity relationships and maximum shortening velocity (Vmax) of muscle fibres from individuals with IIMs (25 type I and 58 type IIA) and healthy controls (66 type I and 27 type IIA) and calculated maximum power output (Wmax) for each fibre. We found significantly higher Vmax (mean ± SEM) of fibres from individuals with IIMs, for both type I (1.40 ± 0.31 fibre lengths/s, n = vs. 0.63 ± 0.13 fibre lengths/s; p = 0.0019) and type IIA fibres (2.00 ± 0.17 fibre lengths/s vs 0.77 ± 0.10 fibre lengths/s; p < 0.0001). Furthermore, Wmax (mean ± SEM) was maintained compared to fibres from healthy controls, again for both type I and type IIA fibres (4.10 ± 1.00 kN/m2·fibre lengths/s vs. 2.00 ± 0.16 kN/m2·fibre lengths/s; p = ns and 9.00 ± 0.64 kN/m2·fibre lengths/s vs. 6.00 ± 0.67 kN/m2·fibre lengths/s; p = ns respectively). In addition, type I muscle fibres from individuals with IIMs was able to develop maximum power output at lower relative force. The findings of this study suggest that compensatory responses to maintain power output, including increased maximum shortening velocity and improved efficiency, may occur in muscle of individuals with IIMs. The mechanism underlying this response is unclear, and different hypotheses are discussed.

Simultaneous loss of skeletal muscle myosin heavy chain IIx and IIb causes severe skeletal muscle hypoplasia in postnatal mice.

The skeletal muscle myosin heavy chain (MyHC) is a fundamental component of the sarcomere structure and muscle contraction. Two of the three adult fast MyHCs, MyHC-IIx and MyHC-IIb, are encoded by Myh1 and Myh4, respectively. However, skeletal muscle disorders have not yet been linked to these genes in humans. MyHC-IIb is barely detectable in human skeletal muscles. Thus, to characterize the molecular function of skeletal muscle MyHCs in humans, investigation of the effect of simultaneous loss of MyHC-IIb and other MyHCs on skeletal muscle in mice is essential. Here, we generated double knockout (dKO) mice with simultaneous loss of adult fast MyHCs by introducing nonsense frameshift mutations into the Myh1 and Myh4 genes. The dKO mice appeared normal after birth and until 2 weeks of age but showed severe skeletal muscle hypoplasia after 2 weeks. In 3-week-old dKO mice, increased expression of other skeletal muscle MyHCs, such as MyHC-I, MyHC-IIa, MyHC-neo, and MyHC-emb, was observed. However, these expressions were not sufficient to compensate for the loss of MyHC-IIb and MyHC-IIx. Moreover, the aberrant sarcomere structure with altered expression of sarcomere components was observed in dKO mice. Our findings imply that the simultaneous loss of MyHC-IIb and MyHC-IIx is substantially detrimental to postnatal skeletal muscle function and will contribute to elucidating the molecular mechanisms of skeletal muscle wasting disorders caused by the loss of skeletal muscle MyHCs.

Preoperative diagnosis of sarcopenia and postoperative outcome in patients with non-small-cell lung cancer.

Sarcopenia is a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality [1]. In 1989, Irwin Rosenberg proposed the term ‘sarcopenia’ (Greek ‘sarx’ or flesh + ‘penia’ or loss) to describe this age-related decrease in muscle mass. Sarcopenia is now formally recognized as a muscle disease with an ICD-10-MC Diagnosis Code. In recent years, the number of sarcopenia-related studies has increased rapidly: 241 in 2010, 1112 in 2016 and 3152 in 2021, according to a PubMed search on ‘sarcopenia’. This rapid increase in research on sarcopenia may reflect increases in aged populations worldwide. Sarcopenia is classified into primary or secondary based on its cause. Primary sarcopenia is mainly related to ageing, while secondary sarcopenia has multiple contributing factors, such as low activity, nutrition and diseases including heart disease, pulmonary disease and malignant disease. The European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia in 2010 as the presence of both low muscle mass and low muscle function (strength or performance) [2]. In 2018, the EWGSOP met again, updating the definition to reflect current scientific and clinical evidence [1]. It emphasized muscle weakness in case identification, with muscle mass measurements as diagnosis confirmation, and physical performance as a severity indicator. The updated EWGSOP2 recommendation aims to increase sarcopenia awareness and risks, promoting early detection and treatment by healthcare professionals treating patients at risk of sarcopenia.

Adiponectin Is a Contributing Factor of Low Appendicular Lean Mass in Older Community-Dwelling Women: A Cross-Sectional Study.

Inflammation is a chronic, sterile, low-grade inflammation that develops with advanced age in the absence of overt infection and may contribute to the pathophysiology of sarcopenia, a progressive and generalized skeletal muscle disorder. Furthermore, a series of biomarkers linked to sarcopenia occurrence have emerged. To aid diagnostic and treatment strategies for low muscle mass in sarcopenia and other related conditions, the objective of this work was to investigate potential biomarkers associated with appendicular lean mass in community-dwelling older women. This is a cross-sectional study with 71 older women (75 ± 7 years). Dual-energy X-ray absorptiometry was used to assess body composition. Plasmatic blood levels of adipokines (i.e., adiponectin, leptin, and resistin), tumor necrosis factor (TNF) and soluble receptors (sTNFr1 and sTNFr2), interferon (INF), brain-derived neurotrophic factor (BDNF), and interleukins (IL-2, IL-4, IL-5, IL-6, IL-8, and IL-10) were determined by enzyme-linked immunosorbent assay. Older women with low muscle mass showed higher plasma levels of adiponectin, sTNFr1, and IL-8 compared to the regular muscle mass group. In addition, higher adiponectin plasma levels explained 14% of the lower appendicular lean mass. High adiponectin plasmatic blood levels can contribute to lower appendicular lean mass in older, community-dwelling women.

Assessing the Effects of Dietary Protein Supplementation on Sarcopenia in Community-Dwelling Older Adults.

Sarcopenia, an age-associated skeletal muscle disorder characterized by muscle loss, is associated with disability in elderly populations. This literature review summarizes the impact of protein intake and supplementation on the indicators of severe sarcopenia-muscle mass, muscle strength, and physical function in community-dwelling older adults. We performed a literature search on PubMed, EMBASE, and MedLine, and included studies that evaluated the effects of protein intake with or without exercise intervention and on sarcopenia in community-dwelling older adults. Information regarding study participants, protein intervention, and sarcopenia-related outcomes were collected. Protein supplementation with or without exercise positively improves muscle mass, and aspects of muscle strength and physical function in sarcopenic and pre-frail older adults, while it elicited inconclusive effects in healthy populations. Greater dietary animal-based and soy-based protein diets can improve muscle mass in older adults. In conclusion, protein supplementation can improve muscle mass and reduce the risk of sarcopenia in sarcopenia and pre-frail older adults, while future studies should continue to investigate the effects of protein supplementation on indicators of sarcopenia in healthy older adults.

Muscle Strength, but Not Muscle Mass, Is Associated with Left Ventricular Diastolic Function during Aging in Chinese.

Sarcopenia, a progressive and systemic skeletal muscle disorder, is closely related with the incidence of cardiovascular disease (CVD) and CVD-related mortality, but its association with cardiac structure and function during aging remains unclear, particularly in the absence of serious cardiovascular diseases. This study aimed to investigate the correlation of muscle mass and muscle strength, the main components of sarcopenia, with left ventricular mass and function in Chinese subjects.A total of 265 men and 70 women (aged 25-95 years) without serious diseases that could have pronounced impact on muscle and/or cardiovascular system were included. Left ventricular mass and function were assessed by echocardiography and muscle mass and grip strength were evaluated by dual-energy X-ray absorptiometry and a Jamar hand dynamometer, respectively.Grip strength and left ventricular diastolic function, rather than left ventricular mass, demonstrated age-dependent decline in both genders. Muscle mass in males and left ventricular systolic function in females declined with age. In the multivariate-adjusted model, grip strength rather than the relative appendicular skeletal muscle mass (RASM) was positively associated with E/A ratio (r = 0.154, P = 0.019) and e´-av (r = 0.175, P = 0.008), but was negatively correlated with E/e´-av ratio (r = -0.136, P = 0.038). No significant correlation was observed between RASM, grip strength and left ventricular mass, left ventricular ejection fraction or left ventricular fractional shortening. Higher grip strength is independently associated with better left ventricular diastolic function in Chinese during aging.

Determination of skeletal muscle mass by aspartate aminotransferase / alanine aminotransferase ratio, insulin and FSH in Chinese women with sarcopenia

Background:Sarcopenia is an age-related skeletal muscle disorder that involves a loss of muscle mass or strength and physiological function. Skeletal muscle deteriorates in both quantity and quality. The endocrine system is an important regulator of muscle metabolism. Therefore, we aimed to explore the relationship between biochemical markers and muscle mass in sarcopenia.Methods:We used the AWGS 2014 as the diagnostic criteria for sarcopenia, considering both the loss in muscle mass, muscle strength and physical performance. A total of 2837 elderly female participants over 50 years of age from the West China Health and Aging Trend (WCHAT) study were included. Insulin, glucose, 25(OH)VD, procalcitonin, alanine aminotransferase, aspartate aminotransferase, total protein, prealbumin, albumin, thyroid-stimulating hormone, free triiodothyronine, free tetraiodothyronine, triglycerides, cholesterol, high-density lipoprotein, very low-density lipoprotein, cortisol, and follicle-stimulating hormone were measured. Based on the findings of univariate analysis, multivariate regression and receiver operating characteristic (ROC) curves were established.Results:Participants with sarcopenia had significantly lower free triiodothyronine, insulin, total protein, albumin, prealbumin, albumin/prealbumin ratio (A/G), alanine aminotransferase, triglycerides, and very low-density lipoprotein concentrations (P < 0.05). Compared with those without sarcopenia, those with sarcopenia had significantly higher free tetraiodothyronine, cortisol, follicle-stimulating hormone (FSH), aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT), and high-density lipoprotein concentrations (P < 0.05). Insulin (OR = 0.854), FSH (OR = 1.016), and the AST/ALT ratio (OR = 1.819) were independent risk factors for low muscle mass (P < 0.001). The AUC of insulin was the highest, followed by the AST/ALT ratio and FSH (0.691, 0.671, and 0.634, respectively), and the AUC of the mixture of the above three reached 0.736.Conclusion:In this cross-sectional study of elderly Chinese females aged over 50 years from the WCHAT, FSH, insulin, and AST/ALT ratio were associated with sarcopenia and risk factors for low muscle mass.

Edukasi Latihan Core Stability terhadap Nyeri Punggung Bawah pada Pembatik Kajang Lako Kota Jambi

The batik makers tend to be in a long sitting position followed by the unergonomic position of the batik makers, the way they work, all of which still use the manual method, will certainly cause a lot of complaints or skeletal muscle disorders. One of the triggering factors for these mechanical disorders is prolonged sitting according to research showing about 39.5-60% of adults experience low back pain due to prolonged sitting for 1.5 hours - 5 hours. One of the jobs at risk for NPB is batik. Batik craftsmen usually have a static nature of work that is carried out within 8 hours per day in a sitting condition. Static muscle contractions for 8 hours in a sitting condition can increase muscle and spinal ligament tension. Community service activities were carried out in June 2022 with the method of discussing and delivering materials and leaflets related to the bad ergonomic effects that lead to lower back pain and demonstrating core stability exercises. This community service aims to be used as a source of knowledge for mothers of batik craftsmen at the Kajang Lako batik studio across the city of Jambi. The results of the evaluation through the question and answer session were that the batik craftsmen had understood how to practice core stability correctly and were able to do it independently.

Identification of Risk Work Accident on The Making Process Tofu Study Case UD. Ainul Yaqin Wringinanom Gresik

Introduction: In the process of making tofu, there is a risk of danger that causes work accidents and occupational diseases to occur. Hazard risks can occur from environmental factors and the workers themselves. Objective: Therefore, this study aims to identify a description of the risk of work accidents in the process of making tofu at UD. Ainul Yaqin. Method: This research is qualitative research while the data obtained from the results of observations and interviews. There were 6 informants involved in the study consisting of 1 supervisor and 5 workers. Data analysis using JSA method. Result and Discussion: The identification results show that there are 23 hazards in the process of making tofu at UD. Ainul Yaqin there are physical hazards, ergonomic hazards, biological hazards and chemical hazards. The risk assessment is categorized as very high 3, high 10, medium 7 and low 3. The control efforts provided are not fully based on the control hierarchy, namely elimination, substitution, engineering control, administrative and personal protective equipment (PPE). Conclusion: The conclusions from the results of the study indicate that there is a risk of slipping, falling, tripping, slipping, itching, minor injuries, hearing loss, eye irritation, physical fatigue and skeletal muscle disorders experienced by workers in the process of making tofu. The industry should improve the conditions of the work environment so as to minimize the occurrence of work accidents and occupational diseases.

Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders.

Mitochondria are an important energy source in skeletal muscle. A main function of mitochondria is the generation of ATP for energy through oxidative phosphorylation (OXPHOS). Mitochondrial defects or abnormalities can lead to muscle disease or multisystem disease. Mitochondrial dysfunction can be caused by defective mitochondrial OXPHOS, mtDNA mutations, Ca2+ imbalances, mitochondrial-related proteins, mitochondrial chaperone proteins, and ultrastructural defects. In addition, an imbalance between mitochondrial fusion and fission, lysosomal dysfunction due to insufficient biosynthesis, and/or defects in mitophagy can result in mitochondrial damage. In this review, we explore the association between impaired mitochondrial function and skeletal muscle disorders. Furthermore, we emphasize the need for more research to determine the specific clinical benefits of mitochondrial therapy in the treatment of skeletal muscle disorders.

Association between oral intake magnesium and sarcopenia: a cross-sectional study

BackgroundSarcopenia is a common skeletal muscle disorder in the elderly population. The patients with sarcopenia increased the cost of care and the risk for hospitalization. Magnesium deficiency might increase reactive oxygen species and protein damage. The purpose of our study was to demonstrate the relation between oral intake magnesium and sarcopenia by European Working Group on Sarcopenia in Older People (EWGSOP) 2 definition.MethodsOur study included 2532 participants with 1310 males and 1222 females. The multiple logistic regression model was designed to test the cross-sectional protective outcome of oral intake magnesium for sarcopenia.ResultsOral intake magnesium had a protective outcome with sarcopenia (odd ratio (OR) = 0.997, 95% CI = 0.996, 0.998, P < 0.001). After fully adjusted, the significance persisted with OR = 0.998 (95% CI = 0.996, 0.999, P < 0.001).ConclusionResults of the present study showed the dose dependent relationship between oral intake magnesium and sarcopenia. Sufficient oral intake magnesium might prevent patient from sarcopenia.

Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle.

Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin–proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.

Autophagy in striated muscle diseases.

Impaired biomolecules and cellular organelles are gradually built up during the development and aging of organisms, and this deteriorating process is expedited under stress conditions. As a major lysosome-mediated catabolic process, autophagy has evolved to eradicate these damaged cellular components and recycle nutrients to restore cellular homeostasis and fitness. The autophagic activities are altered under various disease conditions such as ischemia-reperfusion cardiac injury, sarcopenia, and genetic myopathies, which impact multiple cellular processes related to cellular growth and survival in cardiac and skeletal muscles. Thus, autophagy has been the focus for therapeutic development to treat these muscle diseases. To develop the specific and effective interventions targeting autophagy, it is essential to understand the molecular mechanisms by which autophagy is altered in heart and skeletal muscle disorders. Herein, we summarize how autophagy alterations are linked to cardiac and skeletal muscle defects and how these alterations occur. We further discuss potential pharmacological and genetic interventions to regulate autophagy activities and their applications in cardiac and skeletal muscle diseases.

Atrophic skeletal muscle fibre-derived small extracellular vesicle miR-690 inhibits satellite cell differentiation during ageing.

Sarcopenia is a common and progressive skeletal muscle disorder characterized by atrophic muscle fibres and contractile dysfunction. Accumulating evidence shows that the number and function of satellite cells (SCs) decline and become impaired during ageing, which may contribute to impaired regenerative capacity. A series of myokines/small extracellular vesicles (sEVs) released from muscle fibres regulate metabolism in muscle and extramuscular tissues in an autocrine/paracrine/endocrine manner during muscle atrophy. It is still unclear whether myokines/sEVs derived from muscle fibres can affect satellite cell function during ageing. Aged mice were used to investigate changes in the myogenic capacity of SCs during ageing-induced muscle atrophy. The effects of atrophic myotube-derived sEVs on satellite cell differentiation were investigated by biochemical methods and immunofluorescence staining. Small RNA sequencing was performed to identify differentially expressed sEV microRNAs (miRNAs) between the control myotubes and atrophic myotubes. The target genes of the miRNA were predicted by bioinformatics analysis and verified by luciferase activity assays. The effects of identified miRNA on the myogenic capacity of SCs in vivo were investigated by intramuscular injection of adeno-associated virus (AAV) to overexpress or silence miRNA in skeletal muscle. Our study showed that the myogenic capacity of SCs was significantly decreased (50%, n=6, P<0.001) in the tibialis anterior muscle of aged mice. We showed that atrophic myotube-derived sEVs inhibited satellite cell differentiation in vitro (n=3, P<0.001) and in vivo (35%, n=6, P<0.05). We also found that miR-690 was the most highly enriched miRNA among all the screened sEV miRNAs in atrophic myotubes [Log2 (Fold Change)=7, P<0.001], which was verified in the atrophic muscle of aged mice (threefold, n=6, P<0.001) and aged men with mean age of 71±5.27years (2.8-fold, n=10, P<0.001). MiR-690 can inhibit myogenic capacity of SCs by targeting myocyte enhancer factor 2, including Mef2a, Mef2c and Mef2d, in vitro (n=3, P<0.05) and in vivo (n=6, P<0.05). Specific silencing of miR-690 in the muscle can promote satellite cell differentiation (n=6, P<0.001) and alleviate muscle atrophy in aged mice (n=6, P<0.001). Our study demonstrated that atrophic muscle fibre-derived sEV miR-690 may inhibit satellite cell differentiation by targeting myocyte enhancer factor 2 during ageing.

Sarcopenia definition, diagnosis and treatment: consensus is growing.

Sarcopenia is a skeletal muscle disorder that commonly occurs with advancing age as well as with a number of long-term conditions. Recognition in clinical practice is relatively recent but important because of the association between sarcopenia and a range of adverse effects on health including impaired mobility, increased morbidity and mortality. Originally characterised as loss of muscle mass, the definition has evolved to focus on loss of skeletal muscle function, particularly strength, through a number of international definitions such as that of the European Working Group on Sarcopenia in Older People most recently revised in 2019. Progress in the decades ahead is likely to be seen with regard to use of routine health data, prescription of resistance exercise, translation of biology and epidemiology into first in man studies for new treatments, and focus on sarcopenia in low and middle-income countries. Immediate next steps include the newly formed Global Leadership Initiative on Sarcopenia to develop international consensus on definition and diagnosis.

I.02 Titin – The newly-emerged "titan" of the cardiac and skeletal muscle disease world

The advent of massively parallel sequencing made the routine analysis of enormous genes like <i>TTN</i> (titin) - the gene that encodes the largest protein in nature - finally feasible. As a direct consequence of the increasing use of this technology in the clinical diagnostic setting, it is now abundantly clear that <i>TTN</i> mutations are responsible several important skeletal muscle and cardiac disorders. Many of these disorders have a devastating lifelong impact on affected individuals and their families and are therefore health system priorities. We now know that heterozygous truncating <i>TTN</i> mutations are the most common genetic cause of dilated cardiomyopathy. In addition, heterozygous mutations in two very specific regions of <i>TTN</i> result in two different adult-onset skeletal muscle disorders: tibial muscular dystrophy and hereditary myopathy with early respiratory failure. Recessive titinopathies caused by mutations in both copies of <i>TTN</i> have recently emerged as one of the most common causes of congenital or early-onset muscle disease. Biallelic <i>TTN</i> mutations have also been identified in a growing number of patients with adolescent- and occasionally adult-onset muscle weakness. There are currently no available titinopathy drug treatments. Management is therefore limited to supportive care. In addition, it is strongly suspected that a significant number of "true" titinopathy patients remain without a genetic diagnosis because their <i>TTN</i> mutations have been missed by standard diagnostic approaches. Our understanding of the transcript- and protein-level impacts of patient mutations and the underlying basis of observed differences in clinical severity is also limited. This presentation will focus on recent clinical and research-based developments in the titinopathy field. We will also examine best practice <i>TTN</i> diagnostic approaches, challenges, and pitfalls. Likely future directions in titinopathy diagnosis, research and treatment development will also be explored.