Decline In Skeletal Muscle Mass Research Articles

The effects of omega-3 polyunsaturated fatty acids on muscle and whole-body protein synthesis: a systematic review and meta-analysis.

Sarcopenia describes the age-related decline in skeletal muscle mass and strength that is driven, at least in part, by an imbalance between rates of muscle protein synthesis (MPS) and muscle protein breakdown. An expanding body of literature has examined the effect of omega-3 polyunsaturated fatty acid (n-3 PUFA) ingestion on MPS rates in older adults, with mixed findings. The aim of this systematic review and meta-analysis was to investigate the effectiveness of n-3 PUFA ingestion in stimulating rates of MPS and whole-body protein synthesis in healthy adults and clinical populations. Searches were conducted of the PubMed, Web of Science, Cochrane Library, and Scopus databases from inception until December 2022 for articles on randomized controlled trials comparing the effect of n-3 PUFA ingestion vs a control or placebo on rates of MPS and whole-body protein synthesis. The search yielded 302 studies, of which 8 were eligible for inclusion. The random effects inverse-variance model was used and standardized mean differences (SMDs) with 95%CIs were calculated to assess the pooled effect. Risk of bias was assessed by the Cochrane Risk-of-Bias 2 tool. The main analysis indicated no effect of n-3 PUFA supplementation on MPS rates (k = 6; SMD: 0.03; 95%CI, -0.35 to 0.40; I2 = 30%; P = .89). Subgroup analysis based on age, n-3 PUFA dose, duration of supplementation, and method used to measure fractional synthetic rate also revealed no effect of n-3 PUFA ingestion on MPS. In contrast, the main analysis demonstrated an effect of n-3 PUFA ingestion on increasing whole-body protein synthesis rates (k = 3; SMD: 0.51; 95%CI, 0.12-0.90; I2 = 0%; P = .01). n-3 PUFA ingestion augments the stimulation of whole-body protein synthesis rates in healthy adults and clinical populations. PROSPERO registration no. 42022366986.

Association between Sarcopenia and Balance in Patients Undergoing Inpatient Rehabilitation after Hip Fractures: A Retrospective Cohort Study.

Background and Objectives: Sarcopenia is characterized by a decline in skeletal muscle mass, strength, and function and is associated with advancing age. This condition has been suggested as a factor that negatively influences the functional outcomes of patients with hip fractures. However, the association between sarcopenia and balance impairment in patients undergoing inpatient rehabilitation after hip fractures remains unclear. In this retrospective cohort study, we aimed to investigate the impact of sarcopenia on balance outcomes in patients undergoing inpatient rehabilitation following hip fractures. Materials and Methods: Baseline sarcopenia was diagnosed using skeletal muscle mass index and handgrip strength, with cut-off values recommended by the Asian Working Group for Sarcopenia. The primary outcome was balance, which was assessed using the Berg Balance Scale (BBS) at the time of discharge. A multiple linear regression model analyzed the association between sarcopenia and balance. The model was adjusted for age, sex, comorbidities, and cognitive function. Results: Among the 62 patients (mean age: 78.2; sex: 75.8% women), 24.2% had sarcopenia. Patients with sarcopenia had significantly lower BBS scores than did those without sarcopenia (41 vs. 49 points, p = 0.004). Multiple linear regression analysis revealed that baseline sarcopenia was independently associated with BBS scores at discharge (β = -0.282, p = 0.038). Conclusions: Following inpatient rehabilitation, patients with baseline sarcopenia had inferior balance outcomes than did those without sarcopenia at discharge. Sarcopenia should be assessed on admission to consider and provide additional care for those with a higher risk of poor functional outcomes. More studies are needed to investigate the association between sarcopenia and functional outcomes, examine the impact of sarcopenia treatment on these outcomes, and reduce the risk of recurrent falls and fractures in patients with hip fractures.

Aging-Related Sarcopenia: Metabolic Characteristics and Therapeutic Strategies.

The proportion of the elderly population is gradually increasing as a result of medical care advances, leading to a subsequent surge in geriatric diseases that significantly impact quality of life and pose a substantial healthcare burden. Sarcopenia, characterized by age-related decline in skeletal muscle mass and quality, affects a considerable portion of older adults, particularly the elderly, and can result in adverse outcomes such as frailty, fractures, bedridden, hospitalization, and even mortality. Skeletal muscle aging is accompanied by underlying metabolic changes. Therefore, elucidating these metabolic profiles and specific mechanisms holds promise for informing prevention and treatment strategies for sarcopenia. This review provides a comprehensive overview of the key metabolites identified in current clinical studies on sarcopenia and their potential pathophysiological alterations in metabolic activity. Besides, we examine potential therapeutic strategies for sarcopenia from a perspective focused on metabolic regulation.

Transcriptome-based deep learning analysis identifies drug candidates targeting protein synthesis and autophagy for the treatment of muscle wasting disorder

Sarcopenia, the progressive decline in skeletal muscle mass and function, is observed in various conditions, including cancer and aging. The complex molecular biology of sarcopenia has posed challenges for the development of FDA-approved medications, which have mainly focused on dietary supplementation. Targeting a single gene may not be sufficient to address the broad range of processes involved in muscle loss. This study analyzed the gene expression signatures associated with cancer formation and 5-FU chemotherapy-induced muscle wasting. Our findings suggest that dimenhydrinate, a combination of 8-chlorotheophylline and diphenhydramine, is a potential therapeutic for sarcopenia. In vitro experiments demonstrated that dimenhydrinate promotes muscle progenitor cell proliferation through the phosphorylation of Nrf2 by 8-chlorotheophylline and promotes myotube formation through diphenhydramine-induced autophagy. Furthermore, in various in vivo sarcopenia models, dimenhydrinate induced rapid muscle tissue regeneration. It improved muscle regeneration in animals with Duchenne muscular dystrophy (DMD) and facilitated muscle and fat recovery in animals with chemotherapy-induced sarcopenia. As an FDA-approved drug, dimenhydrinate could be applied for sarcopenia treatment after a relatively short development period, providing hope for individuals suffering from this debilitating condition.

O101: Current guidelines on physical activity do not prevent skeletal muscle loss and physical decline prior to Oesophagogastric cancer surgery: a new benchmark for prehabilitation?

Abstract Prehabilitation is being widely adopted to optimise physical health prior to surgery. However, there remains a lack of consensus regarding exercise type and intensity with current guidance extrapolated from generic, non-cancer populations. The WHO and American College of Sports Medicine (ACSM) recommend 600-1200 Metabolic Equivalent minutes (MET-mins) per week of physical activity (PA) but the effectiveness of this recommendation in cancer populations is unknown. Patients undergoing treatment for Oesophagogastric cancer were prospectively recruited. International Physical Activity Questionnaire (IPAQ) quantified PA at baseline and throughout treatment. Two cohorts were defined (lowPA and highPA) based on ACSM cut-off of 1200 MET-mins/week. Outcome measures were physical function (1 minute sit-to-stand, 1mSTS), CT muscle mass, chemotoxicity, and failure to complete planned treatment. 38 patients completed all study assessments (highPA n=20, lowPA n=18) with no difference in baseline characteristics or disease stage between groups. LowPA group showed declines in 1mSTS performance following chemotherapy, whereas the highPA group improved (mean difference -4 versus +10, p=0.001). Whilst both saw a decline in skeletal muscle mass, the lowPA group lost significantly more (mean difference -5.1 versus -1.8, p=0.007). There were trends towards a lower incidence of severe chemotoxicity (30% vs 61%, p=0.054) and failure to complete planned treatment (15% versus 28%, p=.33) in the highPA group. Whilst further research is required to define the most effective prehabilitation strategy, this study is the first to suggest a new benchmark to preserve muscle mass and function is higher than current guidelines and should be considered when developing prehabilitation recommendations.

Mitochondrial Quantity and Quality in Age-Related Sarcopenia.

Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones. A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords. Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent. The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction.

Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.

Sarcopenia and inflammatory bowel disease: current information

With the appearance of the term "sarcopenia" and its definition, updated in 2010 and 2018, an active study of this phenomenon began. Sarcopenia is a generalized, progressive decline in skeletal muscle mass, strength, and performance leading to reduced quality of life, increased risk of falls, hospitalization, and mortality. Initially, loss of muscle mass was considered an age-associated condition. Today, there is growing interest in premature sarcopenia, which is seen in the setting of malignancy, malnutrition, and chronic inflammatory processes, including inflammatory bowel disease (IBD). Data regarding sarcopenia in patients with IBS are limited. However, published studies suggest a relationship between sarcopenia and unfavorable postoperative outcomes, need for surgical treatment, and disease activity. It is worth noting that sarcopenia is a fairly common phenomenon among patients with CKD, and is observed in 20-70% of cases. The nature of nutritional status disorders in patients suffering from CLC is undergoing changes due to the widespread epidemic of obesity. Sarcopenia in such patients may occur under the mask of obesity, remaining undiagnosed for a long time.
 The aim of the review was to analyze the current information on the incidence of sarcopenia in patients with IBS, its impact on the course of the disease and outcomes of surgical treatment. The following issues need to be addressed today: development of diagnostic criteria for the evaluation of sarcopenia in patients with ICD; inclusion of sarcopenia in the existing models of predicting surgical risks; conducting multicenter prospective studies confirming the influence of sarcopenia on the course and activity of ICD.
 Literature search containing information on relevant studies was conducted in PubMed and Google Scholar by keywords: sarcopenia, inflammatory bowel disease, nutritional status, malnutrition, ulcerative colitis, Crohn's disease.

Characterization of Anthropometric Changes in Patients with Relapsed/Refractory Myeloma Treated with BCMA Bispecific Antibody Teclistamab

Introduction: Cancer-associated cachexia is associated with poor survival rates in several cancer types. Multiple Myeloma (MM) preferentially occurs in the elderly and is the most common cancer that causes lytic bone metastasis causing bone pain, fractures, mobility limitations, and falls. Cachexia is projected to be common in myeloma but has not been fully studied. Myeloma treatments including corticosteroids, radiation and alkylators cause muscle loss, while novel immunotherapy is tumor-specific but their impact on cachexia is unknown. We characterize the changes in body composition in patients with relapsed/refractory myeloma treated with BCMA bispecific antibody teclistamab and determine the association between body composition with treatement response and overall survival. Methods: 49 MM patients treated with teclistamab between 2000 and 2021 were included. All were with relapsed/refractory disease after > 4 lines of therapy and received an approved dose and schedule of teclistamab. The response assessment was according to IMWG criteria. Body weight, body mass index (BMI), tumor burden, and organ function were assessed at baseline and post-treatment. Standard-of-care abdominopelvic CT or PET/CT scans at baseline and at last known follow up were analyzed with Data Analysis Facilitation Suite (DAFS) software to quantify skeletal muscle (SKM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Differences between groups were tested using the χ 2 test or paired t-test. Progression free survival (PFS) and overall survival (OS) from the start of teclistamab to progression and death or last follow-up, respectively, were analyzed by the Kaplan-Meier method. Comparisons were made with the log-rank test. Results: Patient characteristics are detailed in Table 1. Based on the WHO definition, 2% were underweight, 16% were normal weight, 19% were overweight and 13% were obese, at baseline. The baseline mean SKM was 105.6 ± 27.8 (Male 122.0 ± 25.3, female 93.4 ± 23.5). SAT and VAT varied widely. Median SAT was 196.5 (range 48.3-558.6), and median VAT was 136.6 (33.09-448.1). Of 32 patients in the obese group, 16 (50%) patients had SKM that was below the mean SKM of the group. Baseline SAT and VAT, but not SKM were correlated with BMI. Twenty-seven of the 49 patients had paired imaging. The absolute changes in skeletal muscle and adipose tissue compartments are shown in Table 2. A majority of patients had a decline in SKM, SAT and VAT post-treatment: mean SKM decrease was 8.9 cm 2 ( p ≤ 0.01), mean SAT decreased 24.3 cm 2 ( p = 0.02) and mean VAT decreased 27.4 cm 2 ( p = 0.03), while BMI and weight were unchanged. Nineteen of 27 (70%) subjects responded to therapy. The changes in SKM, VAT, and SAT loss did not differ significantly between responders and non-responders. 38.8% of patients (19/49) had died by the end of the follow-up. Median follow-up duration was 2.8 years, overall survival was 1.7 years and PFS was 0.9 years. Baseline SKM, SAT, and VAT did not correlate with PFS or OS, but a decline in SMK significantly correlated with a shorter OS (p=0.04); 7/18 patients with decreased SKM and 2/9 patients with unchanged or increased SKM died. Response correlated strongly with overall survival (p=0.002). Conclusions: Body composition analysis of standard CT images may provide clinically relevant information for patients with advanced myeloma. Sarcopenia was common despite high BMI, and a further decline in skeletal muscle mass correlated with shorter survival, regardless of response to tumor-specific immunotherapy. Anthropometric changes should be validated in larger patient cohorts and included in future clinical trials. Further efforts should focus on the maintenance of muscle and visceral adipose tissue in this patient population.

Abstract 14435: Psoas Muscle Index as a Tool to Predict Outcomes in a Pulmonary Hypertension Population Undergoing Pulmonary Thromboendarterectomy

Introduction: Sarcopenia is defined as an overall decline in skeletal muscle mass and has been associated with a range of cardiac pathologies. Psoas Muscle Index (PMI) has emerged as a metric of sarcopenia. We investigated the prognostic value of PMI on six-minute walk distance (6MWD), and length of stay (LOS) in pulmonary hypertension patients following Pulmonary Thromboendarterectomy (PTE). Hypothesis: Sarcopenic patients will have lower 6MWD meters and increased LOS compared to non-sarcopenic patients. Methods: Retrospective chart review of 65 patients with CTEPH who had undergone PTE with CT scans of the abdomen between 2017-2022. Psoas muscle area was measured at the L3 level on CT scan. PMI was calculated using the formula (left psoas area + right psoas area)/height 2 . Patients in the 1 st quartile PMI for their gender were classified as sarcopenic. 1 st quartile PMI values were calculated as 5.34 cm 2 /m 2 for males, and 3.30 cm 2 /m 2 for females. Results: 17 (26%) patients were classified as sarcopenic. There were no significant differences between sarcopenic and non-sarcopenic groups comparing hemodynamics (mean PA 45 vs 42 mmHg, PVR 9 vs 8 WU, CI 2 vs 2.1-l/min/m 3 ), age (61.2 vs 59.7-years), female sex (52.9 vs 55.3%), ethnicity or comorbidities. Regarding 6 minute walk distance (6MWD), the sarcopenic group had significantly lower meters walked than the non-sarcopenic group pre-PTE (220 vs. 322-meters, p=0.049). Following PTE, there was less distinction between groups in 6MWD (347.1 meters vs 345.1, p=0.970). The sarcopenic group increased their 6MWD more than the non-sarcopenic group (137.3 meters vs 43.7, p=0.055). The sarcopenic group had significantly longer overall length of stay (LOS) (27 vs 14-days, p=0.001), and intensive care unit stay (19 days vs. 6-days, p=0.002) than the non-sarcopenic group. Conclusions: Sarcopenia is prevalent in patient with CTEPH. Sarcopenic patients with CTEPH had lower pre-PTE 6MWD, longer ICU stays and overall hospital LOS.

A Basic Review of Sarcopenia Diagnosis

Associated with aging, sarcopenia is characterized by a decline in skeletal muscle mass, muscle strength and physical performance, eventually resulting in reduced physical capability, disability, poor quality of life, mortality in older people and high health care expenditure. The prevalence varies significantly by population characteristics, disease status, diagnostic criteria and measurement tools. It is essential to achieve an accurate diagnosis of sarcopenia for the management plan to be effective. This review briefly discusses the essential steps in diagnosing sarcopenia: Find – Assess – Confirm - Severity. Keywords: sarcopenia, sarcopenia diagnosis, case finding, muscle strength, performance, muscle mass

Unraveling the Multifactorial Etiology and the Potential Strategies to Overcome Sarcopenia

Sarcopenia, characterized by the decline of skeletal muscle mass and function, can have severe consequences for older adults, including disability and frailty. The condition is also linked to various diseases, increased insulin resistance, fatigue, falls, and mortality. Factors such as obesity and myosteatosis (fat infiltration into muscle) play a significant role in driving sarcopenia, particularly in morbidly obese individuals who also have low muscle mass, known as sarcopenic obesity. The Framingham study found additional limitations in function and mobility in individuals with sarcopenic obesity. This literature review aims to provide the potential causes of sarcopenia, with a specific focus on middle-aged adults, the biological processes that lead to muscle loss, methods to mitigate its effects, and how physical activity and nutrition can aid in recovery.

32 An evaluation of a 6 week physiotherapy strength and balance intervention for the older person in primary care

Abstract Background Ageing is associated with a decline in skeletal muscle mass, strength and function, resulting in sarcopenia and frailty. Guidelines for physical activity in older adults recommend multimodal exercise. The aim of this study was to evaluate a group exercise intervention for older adults attending Primary Care Physiotherapy. Methods Participants were over 65 years, independently mobile with or without an aid, and deemed suitable by the referring Physiotherapist. The 6 week intervention based on the Otago programme, with additional upper limb strength training. It was delivered once weekly with additional independent home sessions advised. Outcome measures included SARC-F (Sarcopenia Screening Tool), grip strength, 5 Times Sit to Stand (5XSTS), and Timed Up and Go (TUG). Data was analysed using descriptive statistics. Results 31 participants completed the intervention (22 women and 9 men). Mean age 80 years (SD = 5.6). 52% of participants (n = 16) had a score of ≥4 greater using the SARC-F Tool indicating a need for further evaluation. The mean grip strength for women was 15.70 kg (SD 4.4) suggestive of probable sarcopenia based on EWGSOP2 definition. Mean grip for men of 29 kg (SD = 8) was within normal range. Mean TUG was 13.8 seconds, indicating falls risk. Mean 5XSTS in all age categories was lower than aged matched norms suggesting functional impairment (60–69 years = 11.14 sec, 70–79 years = 18.58 sec, 80–89 years = 17.2 sec). Following intervention, mean grip strength for men improved (33.5 kg, SD = 8.8). Mean grip strength for women improved to within normal range (18.4 kg, SD = 4.3). Mean TUG score improved to 12.6 sec. Mean 5XSTS improved but remained lower than age matched norms (60–69 years 9.84 sec, 70–79 years 16.72 sec, 80–89 years 15.52 sec). Conclusion The study demonstrated the accessibility, feasibility and benefits of a Physiotherapy group strength and balance intervention in Primary Care.

A comprehensive review on the risks assessment and treatment options for Sarcopenia in people with diabetes.

This comprehensive review aims to examine the reciprocal interplay between Type 2 diabetes mellitus (T2DM) and sarcopenia, identify prevailing research gaps, and discuss therapeutic approaches and measures to enhance healthcare practices within hospital settings. A thorough literature review was conducted to gather relevant studies and articles on the relationship between T2DM and sarcopenia. Various databases were searched, including Google Scholar, PubMed, Scopus, and Science Direct databases. The search terms included T2DM, sarcopenia, inflammation, insulin resistance, advanced glycation end products, oxidative stress, muscle dimensions, muscle strength, muscle performance, aging, nutrition, hormone levels, and physical activity. The collected articles were critically analysed to extract key findings and identify gaps in current research. The prevalence and incidence of metabolic and musculoskeletal disorders, notably T2DM and sarcopenia, have surged in recent years. T2DM is marked by inflammation, insulin resistance, accumulation of advanced glycation end products, and oxidative stress, while sarcopenia involves a progressive decline in skeletal muscle mass and function. The review underscores the age-related correlation between sarcopenia and adverse outcomes like fractures, falls, and mortality. Research gaps regarding optimal nutritional interventions for individuals with T2DM and sarcopenia are identified, emphasizing the necessity for further investigation in this area. The reciprocal interplay between T2DM and sarcopenia holds significant importance. Further research is warranted to address knowledge gaps, particularly in utilizing precise measurement tools during clinical trials. Lifestyle modifications appear beneficial for individuals with T2DM and sarcopenia. Additionally, practical nutritional interventions require investigation to optimize healthcare practices in hospital settings. The online version contains supplementary material available at 10.1007/s40200-023-01262-w.

The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?

A gradual decline in skeletal muscle mass and function is closely tied to increased mortality and disease risk during organismal aging. Exercise training is the most effective way to enhance muscle health, but the adaptive response to exercise as well as muscle repair potential is blunted in older individuals. Numerous mechanisms contribute to the loss of muscle mass and plasticity as aging progresses. An emerging body of recent evidence implicates an accumulation of senescent ("zombie") cells in muscle as a contributing factor to the aging phenotype. Senescent cells cannot divide but can release inflammatory factors and create an unfavorable environment for homeostasis and adaptation. On balance, some evidence indicates that cells with senescent characteristics can be beneficial for the muscle adaptive process, specifically at younger ages. Emerging evidence also suggests that multinuclear muscle fibers could become senescent. In this review, we summarize current literature on the prevalence of senescent cells in skeletal muscle and highlight the consequences of senescent cell removal on muscle mass, function, and adaptability. We examine key limitations in the field of senescence specifically in skeletal muscle and identify areas of research that require future investigation.NEW & NOTEWORTHY There is evidence to suggest that senescent "zombie" cells may or may not accrue in aging skeletal muscle. When muscle is perturbed regardless of age, senescent-like cells do appear, and the benefits of removing them could be age-dependent. More work is needed to determine the magnitude of accumulation and source of senescent cells in muscle. Regardless, pharmacological senolytic treatment of aged muscle is beneficial for adaptation.

The effect of combined β-lactoglobulin supplementation and resistance exercise training prior to limb immobilisation on muscle protein synthesis rates in healthy young adults: study protocol for a randomised controlled trial

BackgroundThe decline in skeletal muscle mass experienced following a short-term period (days to weeks) of muscle disuse is mediated by impaired rates of muscle protein synthesis (MPS). Previous RCTs of exercise or nutrition prehabilitation interventions designed to mitigate disuse-induced muscle atrophy have reported limited efficacy. Hence, the aim of this study is to investigate the impact of a complex prehabilitation intervention that combines β-lactoglobulin (a novel milk protein with a high leucine content) supplementation with resistance exercise training on disuse-induced changes in free-living integrated rates of MPS in healthy, young adults.Methods/designTo address this aim, we will recruit 24 healthy young (18–45 years) males and females to conduct a parallel, double-blind, 2-arm, randomised placebo-controlled trial. The intervention group will combine a 7-day structured resistance exercise training programme with thrice daily dietary supplementation with 23 g of β-lactoglobulin. The placebo group will combine the same training programme with an energy-matched carbohydrate (dextrose) control. The study protocol will last 16 days for each participant. Day 1 will be a familiarisation session and days 2–4 will be the baseline period. Days 5–11 represent the ‘prehabilitation period’ whereby participants will combine resistance training with their assigned dietary supplementation regimen. Days 12–16 represent the muscle disuse-induced ‘immobilisation period’ whereby participants will have a single leg immobilised in a brace and continue their assigned dietary supplementation regimen only (i.e. no resistance training). The primary endpoint of this study is the measurement of free-living integrated rates of MPS using deuterium oxide tracer methodology. Measurements of MPS will be calculated at baseline, over the 7-day prehabilitation period and over the 5-day immobilisation period separately. Secondary endpoints include measurements of muscle mass and strength that will be collected on days 4 (baseline), 11 (end of prehabilitation) and 16 (end of immobilisation).DiscussionThis novel study will establish the impact of a bimodal prehabilitation strategy that combines ß-lactoglobulin supplementation and resistance exercise training in modulating MPS following a short-term period of muscle disuse. If successful, this complex intervention may be translated to clinical practice with application to patients scheduled to undergo, for example, hip or knee replacement surgery.Trial registrationNCT05496452. Registered on August 10, 2022.Protocol version: 16-12-2022/1

Increased mitochondrial Ca2+ contributes to health decline with age and Duchene muscular dystrophy in C. elegans.

Sarcopenia is a geriatric syndrome characterized by an age-related decline in skeletal muscle mass and strength. Here, we show that suppression of mitochondrial calcium uniporter (MCU)-mediated Ca2+ influx into mitochondria in the body wall muscles of the nematode Caenorhabditis elegans improved the sarcopenic phenotypes, blunting movement and mitochondrial structural and functional decline with age. We found that normally aged muscle cells exhibited elevated resting mitochondrial Ca2+ levels and increased mitophagy to eliminate damaged mitochondria. Similar to aging muscle, we found that suppressing MCU function in muscular dystrophy improved movement via reducing elevated resting mitochondrial Ca2+ levels. Taken together, our results reveal that elevated resting mitochondrial Ca2+ levels contribute to muscle decline with age and muscular dystrophy. Further, modulation of MCU activity may act as a potential pharmacological target in various conditions involving muscle loss.

Longitudinal transcriptomic analysis of mouse sciatic nerve reveals pathways associated with age-related muscle pathology.

Sarcopenia, the age-associated decline in skeletal muscle mass and strength, has long been considered a disease of muscle only, but accumulating evidence suggests that sarcopenia could originate from the neural components controlling muscles. To identify early molecular changes in nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve, which governs lower limb muscles, in aging mice. Sciatic nerve and gastrocnemius muscle were obtained from female C57BL/6JN mice aged 5, 18, 21 and 24months old (n=6 per age group). Sciatic nerve RNA was extracted and underwent RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were validated using quantitative reverse transcription PCR (qRT-PCR). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups (adjusted P-value<0.05, likelihood ratio test [LRT]) was performed. Pathological skeletal muscle aging was confirmed between 21 and 24months by a combination of molecular and pathological biomarkers. Myofiber denervation was confirmed with qRT-PCR of Chrnd, Chrng, Myog, Runx1 and Gadd45ɑ in gastrocnemius muscle. Changes in muscle mass, cross-sectional myofiber size and percentage of fibres with centralized nuclei were analysed in a separate cohort of mice from the same colony (n=4-6 per age group). We detected 51 significant DEGs in sciatic nerve of 18-month-old mice compared with 5-month-old mice (absolute value of fold change>2; false discovery rate [FDR]<0.05). Up-regulated DEGs included Dbp (log2 fold change [LFC]=2.63, FDR<0.001) and Lmod2 (LFC=7.52, FDR=0.001). Down-regulated DEGs included Cdh6 (LFC=-21.38, FDR<0.001) and Gbp1 (LFC=-21.78, FDR<0.001). We validated RNA-seq findings with qRT-PCR of various up- and down-regulated genes including Dbp and Cdh6. Up-regulated genes (FDR<0.1) were associated with the AMP-activated protein kinase signalling pathway (FDR=0.02) and circadian rhythm (FDR=0.02), whereas down-regulated DEGs were associated with biosynthesis and metabolic pathways (FDR<0.05). We identified seven significant clusters of genes (FDR<0.05, LRT) with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in age-related changes in skeletal muscles and/or sarcopenia initiation including extracellular matrix organization and an immune response (FDR<0.05). Gene expression changes in mouse peripheral nerve were detected prior to disturbances in myofiber innervation and sarcopenia onset. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies are warranted to confirm the disease modifying and/or biomarker potential of the key changes we report here.

Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study

PurposePatients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP).MethodsWe retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation.ResultsCompared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3–22.7) and 10.3 months (95%CI 8.3–18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00–5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01–2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47–3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42–3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95–2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS.ConclusionEarly skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis.