The clinical significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib and PD-1 inhibitors.

Background and aim: Sarcopenia has gained considerable attention in the context of hepatocellular carcinoma, as it has been correlated with a poorer prognosis among patients undergoing sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC). The clinical significance of sarcopenia in first-line advanced HCC patients treated with lenvatinib and programmed death-1 (PD-1) inhibitors needs to be clarified. Methods: Sarcopenia was diagnosed using CT (Computed tomography) or MRI (Magnetic Resonance Imaging), with the psoas muscle index (PMI) as the surrogate marker. Patients were grouped based on sarcopenia presences, and a comparative analysis examined characteristics, adverse events, and prognosis. The Cox regression analysis was applied to identify independent prognostic factors for survival, while nomograms were constructed to predict 1-year survival. Results: Among 180 patients, 46 had sarcopenia. Patients with baseline sarcopenia demonstrated significantly inferior median progression-free survival (mPFS) (3.0 vs. 8.3 months) and median overall survival (mOS) (7.3 vs. 21.6 months). The same results for mPFS (3.3 vs. 9.2 months) and mOS (9.4 vs. 24.2 months) were observed in patients who developed sarcopenia after treatment. Furthermore, significantly higher grade 3 or higher adverse events (AEs) (73.91% vs 41.79%, p<0.001) were recorded in the sarcopenia group compared to the non-sarcopenia group. In the multivariate analysis, distant metastasis, elevated PLR and CRP levels, and low PMI remained independent predictive factors for poor OS. Additionally, skeletal muscle loss remained a significant independent risk factor for PFS. We developed a nomogram incorporating these four indicators, which predicted 12-month survival with a C-index of 0.853 (95% CI, 0.791 - 0.915), aligning well with actual observations. Conclusion: The prognosis of patients with HCC and sarcopenia is significantly worse when treated with lenvatinib and PD-1 inhibitors. The combination regimen of lenvatinib plus PD-1 inhibitors should be cautiously recommended due to the inferior prognosis and higher AEs.

Effects of Ninjin'yoeito on Patients with Chronic Obstructive Pulmonary Disease and Comorbid Frailty and Sarcopenia: A Preliminary Open-Label Randomized Controlled Trial.

Purpose: To present the preliminarily findings regarding the effects of a herbal medicine, Ninjin'yoeito, on comorbid frailty and sarcopenia in patients with chronic obstructive pulmonary disease (COPD). Patients and Methods: Patients with COPD (GOLD II or higher) and fatigue were randomly assigned to Group A (n = 28; no medication for 12 weeks, followed by 12-week administration) or B (n= 25; 24-week continuous administration). Visual analog scale (VAS) symptoms of fatigue, the COPD assessment test (CAT), and the modified Medical Research Council (mMRC) Dyspnea Scale were examined. Physical indices such asknee extension leg strength and walking speed, skeletal muscle mass index (SMI), and respiratory function test were also measured. Results: VAS fatigue scales in Group B significantly improved after 4, 8, and 12 weeks compared to those in Group A (each p<0.001, respectively). Right and left knee extension leg strength in Group B significantly improved after 12 weeks compared to that in Group A (p=0.042 and p=0.037, respectively). The 1-s walking speed for continued to increase significantly over 24 weeks in Group B (p=0.016, p<0.001, p<0.001, p=0.004, p<0.001, and p<0.001 after 4, 8, 12, 16, 20, and 24 weeks, respectively); it also significantly increased after the administration of Ninjin'yoeito in Group A. In Group B, the SMI significantly increased at 12 weeks in patients with sarcopenia (p=0.025). The CAT scores in Group B significantly improved after 12 weeks compared to those in Group A (p=0.006). The mMRC scores in Group B also significantly improved after 8 and 12 weeks compared to those in Group A (p= 0.045 and p <0.001, respectively). The changes in %FEV1.0 in Group B were significantly improved at 12 and 24 weeks (p=0.039 and p=0.036, respectively). Conclusion: Overall, Ninjin'yoeito significantly improved patients' quality of life, physical activity, muscle mass, and possibly lung function, suggesting that Ninjin'yoeito may improve frailty and sarcopenia in patients with COPD.

A Patented Dietary Supplement (Hydroxy-Methyl-Butyrate, Carnosine, Magnesium, Butyrate, Lactoferrin) Is a Promising Therapeutic Target for Age-Related Sarcopenia through the Regulation of Gut Permeability: A Randomized Controlled Trial.

Adequate diet, physical activity, and dietary supplementation with muscle-targeted food for special medical purposes (FSMP) or dietary supplement (DS) are currently considered fundamental pillars in sarcopenia treatment. The aim of this study is to evaluate the effectiveness of a DS (containing hydroxy-methyl-butyrate, carnosine, and magnesium, for its action on muscle function and protein synthesis and butyrate and lactoferrin for their contribution to the regulation of gut permeability and antioxidant/anti-inflammation activity) on muscle mass (assessed by dual X-ray absorptiometry (DXA)), muscle function (by handgrip test, chair test, short physical performance battery (SPPB) test, and walking speed test), inflammation (tumor necrosis factor-alpha (TNF-a), C-reactive protein (CRP), and visceral adipose tissue (VAT)) and gut axis (by zonulin). A total of 59 participants (age 79.7 ± 4.8 years, body mass index 20.99 ± 2.12 kg/m2) were enrolled and randomly assigned to intervention (n = 30) or placebo (n = 28). The skeletal muscle index (SMI) significantly improved in the supplemented group compared to the placebo one, +1.02 (CI 95%: -0.77; 1.26), p = 0.001; a significant reduction in VAT was observed in the intervention group, -70.91 g (-13.13; -4.70), p = 0.036. Regarding muscle function, all the tests significantly improved (p = 0.001) in the supplemented group compared to the placebo one. CRP, zonulin, and TNF-alpha significantly decreased (p = 0.001) in intervention, compared to placebo, -0.74 mg/dL (CI 95%: -1.30; -0.18), -0.30 ng/mL (CI 95%: -0.37; -0.23), -6.45 pg/mL (CI 95%: -8.71; -4.18), respectively. This DS improves muscle mass and function, and the gut muscle has emerged as a new intervention target for sarcopenia.

Cornflower Extract and Its Active Components Alleviate Dexamethasone-Induced Muscle Wasting by Targeting Cannabinoid Receptors and Modulating Gut Microbiota.

Sarcopenia, a decline in muscle mass and strength, can be triggered by aging or medications like glucocorticoids. This study investigated cornflower (Centaurea cyanus) water extract (CC) as a potential protective agent against DEX-induced muscle wasting in vitro and in vivo. CC and its isolated compounds mitigated oxidative stress, promoted myofiber growth, and boosted ATP production in C2C12 myotubes. Mechanistically, CC reduced protein degradation markers, increased mitochondrial content, and activated protein synthesis signaling. Docking analysis suggested cannabinoid receptors (CB) 1 and 2 as potential targets of CC compounds. Specifically, graveobioside A from CC inhibited CB1 and upregulated CB2, subsequently stimulating protein synthesis and suppressing degradation. In vivo, CC treatment attenuated DEX-induced muscle wasting, as evidenced by enhanced grip strength, exercise performance, and modulation of muscle gene expression related to differentiation, protein turnover, and exercise performance. Moreover, CC enriched gut microbial diversity, and the abundance of Clostridium sensu stricto 1 positively correlated with muscle mass. These findings suggest a multifaceted mode of action for CC: (1) direct modulation of the muscle cannabinoid receptor system favoring anabolic processes and (2) indirect modulation of muscle health through the gut microbiome. Overall, CC presents a promising therapeutic strategy for preventing and treating muscle atrophy.

Lipid-Lowering Medications are Associated with Reduced Sarcopenia-Related Quality of Life in Older Adults with Hyperlipidemia.

PURPOSE: Statins medications negatively affect age-associated loss of muscle mass and strength, termed sarcopenia, and neuromuscular junction (NMJ) integrity. However, their association with the sarcopenia-related-quality-of-life (SarQoL) is unknown. METHODS: In this cross-sectional, case control study, we recruited male nonusers (n = 75 and age 75.2 ± 5.9 years) and users (n = 77 and age 77.1 ± 6.2 years) of statins to evaluate SarQoL and handgrip strength (HGS). We also measured plasma C-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation. RESULTS: Statin users had higher CAF22, and lower HGS, and cumulative SarQoL scores than non-users (all p < 0.05). Plasma CAF22 exhibited negative correlations with SarQoL scores for physical and mental health, locomotion, functionality, activities-of-daily-living, and cumulative SarQoL in statins users and non-users (all p < 0.05). Lastly, the cumulative SarQoL scores exhibited positive associations with HGS and gait speed in the study participants (all p < 0.05). CONCLUSIONS: Collectively, statin usage was associated with NMJ degradation and reduced SarQoL. Statins should be cautiously prescribed in patients with sarcopenia with reduced QoL.

Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies.

Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia. However, it is important to consider the variable efficacy and potential side effects associated with these treatments. There are currently no drugs approved by the Food and Drug Administration for sarcopenia. The ongoing research aims to develop more effective strategies in the future. Our review of research on disease mechanisms and drug development will be a valuable contribution to future research endeavors.

Comparing the efficacy of concomitant treatment of resistance exercise and creatine monohydrate versus multiple individual therapies in age related sarcopenia.

Aging-related sarcopenia is a degenerative loss of strength and skeletal muscle mass that impairs quality of life. Evaluating NUDT3 gene and myogenin expression as new diagnostic tools in sarcopenia. Also, comparing the concomitant treatment of resistance exercise (EX) and creatine monohydrate (CrM) versus single therapy by EX, coenzyme Q10 (CoQ10), and CrM using aged rats. Sixty male rats were equally divided into groups. The control group, aging group, EX-treated group, the CoQ10 group were administered (500 mg/kg) of CoQ10, the CrM group supplied (0.3 mg/kg of CrM), and a group of CrM concomitant with resistance exercise. Serum lipid profiles, certain antioxidant markers, electromyography (EMG), nudix hydrolase 3 (NUDT3) expression, creatine kinase (CK), and sarcopenic index markers were measured after 12 weeks. The gastrocnemius muscle was stained with hematoxylin-eosin (H&E) and myogenin. The EX-CrM combination showed significant improvement in serum lipid profile, antioxidant markers, EMG, NUDT3 gene, myogenin expression, CK, and sarcopenic index markers from other groups. The NUDT3 gene and myogenin expression have proven efficient as diagnostic tools for sarcopenia. Concomitant treatment of CrM and EX is preferable to individual therapy because it reduces inflammation, improves the lipid serum profile, promotes muscle regeneration, and thus has the potential to improve sarcopenia.

Equisetum arvense standardized dried extract hinders age-related osteosarcopenia.

Age-associated osteosarcopenia is an unresolved syndrome characterized by the concomitant loss of bone (osteopenia) and skeletal muscle (sarcopenia) tissues increasing falls, immobility, morbidity, and mortality. Unbalanced resorption of bone in the remodeling process and excessive protein breakdown, especially fast type II myosin heavy chain (MyHC-II) isoform and myofiber metabolic shift, are the leading causes of bone and muscle deterioration in the elderly, respectively. Equisetum arvense (EQ) is a plant traditionally recommended for many pathological conditions due to its anti-inflammatory properties. Thus, considering that a chronic low-grade inflammatory state predisposes to both osteoporosis and sarcopenia, we tested a standardized hydroalcoholic extract of EQ in in vitro models of muscle atrophy [C2C12 myotubes treated with proinflammatory cytokines (TNFα/IFNγ), excess glucocorticoids (dexamethasone), or the osteokine, receptor activator of nuclear factor kappa-B ligand (RANKL)] and osteoclastogenesis (RAW 264.7 cells treated with RANKL). We found that EQ counteracted myotube atrophy, blunting the activity of several pathways depending on the applied stimulus, and reduced osteoclast formation and activity. By in silico target fishing, IKKB-dependent nuclear factor kappa-B (NF-κB) inhibition emerges as a potential common mechanism underlying EQ's anti-atrophic effects. Consumption of EQ (500 mg/kg/day) by pre-geriatric C57BL/6 mice for 3 months translated into: i) maintenance of muscle mass and performance; ii) restrained myofiber oxidative shift; iii) slowed down age-related modifications in osteoporotic bone, significantly preserving trabecular connectivity density; iv) reduced muscle- and spleen-related inflammation. EQ can preserve muscle functionality and bone remodeling during aging, potentially valuable as a natural treatment for osteosarcopenia.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia.

Sarcopenia is an age-associated loss of skeletal muscle mass, strength, and function, accompanied by severe adverse health outcomes, such as falls and fractures, functional decline, high health costs, and mortality. Hence, its prevention and treatment have become increasingly urgent. However, despite the wide prevalence and extensive research on sarcopenia, no FDA-approved disease-modifying drugs exist. This is probably due to a poor understanding of the mechanisms underlying its pathophysiology. Recent evidence demonstrate that sarcopenia development is characterized by two key elements: (i) epigenetic dysregulation of multiple molecular pathways associated with sarcopenia pathogenesis, such as protein remodeling, insulin resistance, mitochondria impairments, and (ii) the creation of a systemic, chronic, low-grade inflammation (SCLGI). In this review, we focus on the epigenetic regulators that have been implicated in skeletal muscle deterioration, their individual roles, and possible crosstalk. We also discuss epidrugs, which are the pharmaceuticals with the potential to restore the epigenetic mechanisms deregulated in sarcopenia. In addition, we discuss the mechanisms underlying failed SCLGI resolution in sarcopenia and the potential application of pro-resolving molecules, comprising specialized pro-resolving mediators (SPMs) and their stable mimetics and receptor agonists. These compounds, as well as epidrugs, reveal beneficial effects in preclinical studies related to sarcopenia. Based on these encouraging observations, we propose the combination of epidrugs with SCLI-resolving agents as a new therapeutic approach for sarcopenia that can effectively attenuate of its manifestations.

Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Skeletal muscle mass increases after viral eradication with direct-acting antivirals in patients with chronic hepatitis C: A longitudinal study.

BACKGROUND: Results of studies evaluating the effect of viral eradication following direct-acting antiviral (DDA) therapy on skeletal muscle mass of patients with chronic hepatitis C (CHC) are scarce. AIM: To assess the components of sarcopenia (low muscle mass, low muscle strength and low physical performance) in a cohort of CHC individuals before and after DAA therapy. METHODS: We performed a longitudinal study of patients with CHC who underwent body composition assessment before (T0), and at 12 (T1) and 48 (T2) weeks after DDA therapy. Bioelectrical Impedance Analysis was used to assess skeletal mass muscle (SM) and phase angle (PhA). SM index (SMI) was calculated by dividing the SM by squared height. Muscle function was evaluated by hand grip strength (HGS) and timed up-and-go (TUG) test. Mixed-effects linear regression models were fitted to SMI, HGS and physical performance and were used to test the effect of HCV eradication by DAA. RESULTS: 62 outpatients (mean age, 58.6 ± 10.8 years; 58% with compensated cirrhosis) were included. Significant decreases in liver fibrosis markers and an increase of 0.20 and 0.22 kg/m2 in the SMI were observed at T1 and T2. Following DAA therapy, an increase of one unit of PhA was associated with a reduction of 0.38 min in TUG. CONCLUSION: HCV eradication with DAA therapy was associated with a dynamic reduction of non-invasive markers of liver fibrosis and increased muscle mass in 62 patients with CHC who had an undetectable HCV load at 12 weeks after completion of antiviral treatment.

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.

Branched-chain amino acid supplementation does not improve measures of sarcopenia in cirrhosis: results of a randomised controlled trial.

BACKGROUND: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. AIMS: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. METHODS: We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. RESULTS: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). CONCLUSION: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations. METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection. ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21. TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

Impact of Chinese herbal medicine on sarcopenia in enhancing muscle mass, strength, and function: A systematic review and meta-analysis of randomized controlled trials.

Sarcopenia has become important to the public health with the increase in the aging population in society. However, the therapeutic effects of conventional approaches, including pharmacotherapy, exercise, and nutritional intervention, are far from satisfactory. Chinese herbal medicine is a new treatment format with interesting possibilities in sarcopenia has been widely practiced. The study aims to explore the effectiveness of Chinese herbal medicine in sarcopenia. We comprehensively searched the following electronic databases: Medline, EMBASE, APA PsycInfo, Cochrane Library, Web of Science, PubMed, and Chinese database from the establishment of the database to December 2022 (no language restrictions). Randomized controlled clinical studies on the use of Chinese herbal medicine in sarcopenia were selected in compliance with PRISMA guidelines. Review Manager and Stata were used for statistical analysis and the mean difference and standardized mean difference were adopted. Of 277 identified studies, 17 were eligible and included in our analysis (N = 1440 participants). The results showed that Chinese herbal medicine can improve total efficiency (RR = 1.29, 95% CI [1.21, 1.36], p < 0.00001) in sarcopenia and enhance muscle mass (SMD = 1.02, 95% CI [0.55, 1.50], p < 0.0001), and muscle strength measured by grip strength (SMD = 0.66, 95% CI [0.36, 0.96], p < 0.0001), measured by 60°/s knee extension peak TQ (MD = 5.63, 95% CI [-0.30, 11.57], p = 0.06) and muscle function measured by 6-meter walking speed (SMD = 1.34, 95% CI [0.60, 2.08], p = 0.0004), measured by the short physical performance battery of 1.50%, 95% CI (1.05, 1.95), measured by the EuroQoL 5-dimension of (SMD = 0.27, 95% CI [-0.10, 0.65], p = 0.16), suggesting that Chinese herbal medicine alone or combined with conventional treatment has ameliorating effect on sarcopenia. Chinese herbal medicine is a potential therapeutic strategy in sarcopenia. The funnel plot and Egger's test indicated publication bias. To confirm our conclusions, further high-quality studies should be conducted.

The Current Landscape of Pharmacotherapies for Sarcopenia.

Sarcopenia is a skeletal muscle disorder characterized by progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding an effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia.

Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Ashwagandha Ethanol Extract Attenuates Sarcopenia-Related Muscle Atrophy in Aged Mice.

The investigation focused on the impact of Withania somnifera (ashwagandha) extract (WSE) on age-related mechanisms affecting skeletal muscle sarcopenia-related muscle atrophy in aged mice. Beyond evaluating muscular aspects, the study explored chronic low-grade inflammation, muscle regeneration, and mitochondrial biogenesis. WSE administration, in comparison to the control group, demonstrated no significant differences in body weight, diet, or water intake, affirming its safety profile. Notably, WSE exhibited a propensity to reduce epidermal and abdominal fat while significantly increasing muscle mass at a dosage of 200 mg/kg. The muscle-to-fat ratio, adjusted for body weight, increased across all treatment groups. WSE administration led to a reduction in the pro-inflammatory cytokines TNF-α and IL-1ß, mitigating inflammation-associated muscle atrophy. In a 12-month-old mouse model equivalent to a 50-year-old human, WSE effectively preserved muscle strength, stabilized grip strength, and increased muscle tissue weight. Positive effects were observed in running performance and endurance. Mechanistically, WSE balanced muscle protein synthesis/degradation, promoted fiber differentiation, and enhanced mitochondrial biogenesis through the IGF-1/Akt/mTOR pathway. This study provides compelling evidence for the anti-sarcopenic effects of WSE, positioning it as a promising candidate for preventing sarcopenia pending further clinical validation.