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Sarcopenia is an age-associated disorder characterized by a progressive decline in skeletal muscle mass, strength, and physical function. The condition is linked to low levels of anabolic hormones such as insulin-like growth factor 1 (IGF-1), with its downstream phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT)/ forkhead box protein O3 (FOXO3) signaling pathway. There is growing evidence that resistance training (RT) or vibration training (VT) could improve physical functioning in individuals with sarcopenia. However, the related physiological influence of exercise on sarcopenia remains elusive. This prospective randomized controlled trial will be conducted among 96 participants, aged between 65 and 80 years. In participants, sarcopenia diagnosis will be confirmed based on the Asian Working Group for Sarcopenia criteria, and participants will be randomized into either control, RT, VT, or RVT (combined RT and VT) groups. The intervention will last 12 weeks, with assessments performed at baseline, 12 weeks (after intervention), and 24 weeks (follow-up). The primary outcomes will include skeletal muscle mass, handgrip strength, and gait speed. Secondary outcomes comprise IGF-1 concentrations, PI3K/AKT and FOXO3 protein activity, quality of life, and timed-up-and-go test performance assessments. This clinical study aims to elucidate the potential modulation of molecular mechanisms in vivo for combined RT and VT in sarcopenia patients and to identify the effects of the intervention on physical function. ChiCTR, ChiCTR2400083643. Registered on April 29, 2024.

Background The pathophysiology of sarcopenia is complex and multifactorial and has not been fully elucidated. The impact of resistance training and nutritional support (RTNS) on metabolomics and lipodomics in older adults with sarcopenia remains uncertain. This study aimed to explore potential biomarkers of sarcopenia and clinical indicators of RTNS in older sarcopenic adults. Methods Older individuals diagnosed with sarcopenia through routine health checkups at a community hospital were recruited for a 12‐week randomized controlled trial focusing on RTNS. Plasma metabolomic and lipidomic profiles of 45 patients with sarcopenia and 47 matched controls were analysed using 1H‐nuclear magnetic resonance (1H‐NMR) and liquid chromatography‐mass spectrometer (LC–MS). Results At baseline, the patient and control groups had similar age, sex, and height distribution. The patient group had significantly lower weight, BMI, grip strength, gait speed, skeletal muscle index, lean mass of both the upper and lower limbs, and lower limb bone mass. There was a significant difference in 12 metabolites between the control and patient groups. They are isoleucine (patient/control fold change [FC] = 0.86 ± 0.04, P = 0.0005), carnitine (FC = 1.05 ± 0.01, P = 0.0110), 1‐methylhistamine/3‐methylhistamine (FC = 1.24 ± 0.14, P = 0.0039), creatinine (FC = 0.71 ± 0.04, P < 0.0001), carnosine (FC = 0.71 ± 0.04, P = 0.0007), ureidopropionic acid (FC = 0.61 ± 0.10, P = 0.0107), uric acid (FC = 0.88 ± 0.03, P = 0.0083), PC (18:2/20:0) (FC = 0.69 ± 0.03, P = 0.0010), PC (20:2/18:0) (FC = 0.70 ± 0.06, P = 0.0014), PC (18:1/20:1) (FC = 0.74 ± 0.05, P = 0.0015), PI 32:1 (FC = 4.72 ± 0.17, P = 0.0006), and PI 34:3 (FC = 1.88 ± 0.13, P = 0.0003). Among them, carnitine, 1‐methylhistamine/3‐methylhistamine, creatinine, ureidopropionic acid, uric acid, PI 32:1, and PI 34:3 were first identified. Notably, PI 32:1 had highest diagnostic accuracy (0.938) for sarcopenia. 1‐Methylhistamine/3‐methylhistamine, carnosine, PC (18:2/20:0), PI 32:1, and PI 34:3 levels were not different from the control group after RTNS. These metabolites are involved in amino acid metabolism, lipid metabolism, and the PI3K‐AKT/mTOR signalling pathway through the ingenuity pathway analysis. Conclusions These findings provide information on metabolic changes, lipid perturbations, and the role of RTNS in patients with sarcopenia. They reveal new insights into its pathological mechanisms and potential therapies.

PurposeThe pharmacokinetic properties of plasma NO3− and its reduced metabolite, NO2−, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO3− ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials.MethodsLinear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO3− and NO2− concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development.ResultsA population pharmacokinetic model relating NO3− and NO2− concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO3− delivery. Covariate analysis revealed intersubject variability in NO3− exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients.ConclusionsExtension of the present first-generation model, to ultimately optimize NO3− dose versus pharmacological effects, is warranted.

Background The optimal exercise regimen for alleviating sarcopenia remains uncertain. This study aimed to investigate the efficacy of high‐intensity interval training (HIIT) over moderate‐intensity continuous training (MICT) in ameliorating sarcopenia. Methods We conducted a randomized crossover trial to evaluate plasma proteomic reactions to acute HIIT (four 4‐min high‐intensity intervals at 70% maximal capacity alternating with 4 min at 30%) versus MICT (constant 50% maximal capacity) in inactive adults. We explored the relationship between a HIIT‐specific protein relative to MICT, identified via comparative proteomic analysis, eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and sarcopenia in a paired case–control study of elderly individuals (aged over 65). Young (3 months old) and aged (20 months old) mice were randomized to sedentary, HIIT and MICT groups (five sessions/week for 4 weeks; n = 8 for each group). Measurements included skeletal muscle index, hand grip strength, expression of atrophic markers Atrogin1 and MuRF1 and differentiation markers MyoD, myogenin and MyHC‐II via western blotting. We examined the impact of EEF1E1 siRNA and recombinant protein on D‐galactose‐induced myoblast senescence, measuring senescence‐associated β‐galactosidase and markers like p21 and p53. Results The crossover trial, including 10 sedentary adults (32 years old, IQR 31–32) demonstrated significant alterations in the abundance of 21 plasma proteins after HIIT compared with MICT. In the paired case–control study of 84 older adults (84 years old, IQR 69–81; 52% female), EEF1E1 was significantly increased in those with sarcopenia compared to those without (14.68 [95%CI, 2.02–27.34] pg/mL, p = 0.03) and was associated with skeletal muscle index (R2 = 0.51, p < 0.001) and hand grip strength (R2 = 0.54, p < 0.001). In the preclinical study, aged mice exhibited higher EEF1E1 mRNA and protein levels in skeletal muscle compared to young mice, accompanied by a lower muscle mass and strength, increased cellular senescence and protein degradation markers and reduced muscle differentiation efficiency (all p < 0.05). HIIT reduced EEF1E1 expression and mitigated age‐related muscle decline and atrophy in aged mice more effectively than MICT. Notably, EEF1E1 downregulation via siRNA significantly counteracted D‐galactose‐induced myoblast senescence as evidenced by reduced markers of muscle protein degradation and improved muscle differentiation efficiency (all p < 0.05). Conversely, treatments that increased EEF1E1 levels accelerated the senescence process (p < 0.05). Further exploration indicated that the decrease in EEF1E1 was associated with increased SIRT1 level and enhanced autophagy. Conclusions This study highlights the potential of HIIT as a promising approach to prevent and treat sarcopenia while also highlighting EEF1E1 as a potential intervention target.

This study evaluated the effect of resistance training (RT) volume on muscular strength and on indicators of abdominal adiposity, metabolic risk, and inflammation in post-menopausal women (PW). Thirty-two volunteers were randomly allocated into the following three groups: control (CT, no exercise, n  = 11), low-volume RT (LV, three sets/exercise, n  = 10), and high-volume RT (HV, six sets/exercise, n  = 11). The LV and HV groups performed eight exercises at 70 % of one maximal repetition, three times a week, for 16 weeks. Muscular strength and indicators of abdominal adiposity, metabolic risk, and inflammation were measured at baseline and after 16 weeks. No differences were found in baseline measures between the groups. The PW showed excess weight and fat percentage (F%), large waist circumference (WC), high waist-hip ratio (WHR), and hypercholesterolemia and borderline values of glycated hemoglobin (HbA1c%). Following the RT, a similar increase in muscle strength and reduction in F% from baseline were found in both trained groups. In HV, a decrease in total cholesterol, LDL-c, WC, and WHR was noted. Moreover, the HV showed a lower change (delta%) of interleukin-6 (IL-6) when compared to CT (HV = 11.2 %, P 25–75  = −7.6–28.4 % vs. CT = 99.55 %, P 25–75  = 18.5–377.0 %, p  = 0.049). In LV, a decrease was noted for HbA1c%. There were positive correlations (delta%) between WHR and IL-6 and between IL-6 and TC. These results suggest that while a low-volume RT improves HbA1c%, F%, and muscular strength, a high-volume RT is necessary to improve indicators of abdominal adiposity and lipid metabolism and also prevent IL-6 increases in PW.

Evolutionary pressures to protect against food scarcity likely resulted in highly-conserved pathways designed to minimize energy expenditure, one of which involves the minimization of muscle mass; these mechanisms may be counter-productive in a modern world suffering from obesity and sarcopenia. Growth differentiation factor 8 (GDF8)/myostatin, acting via ActRIIA/B receptors, is the best-characterized negative regulator of muscle mass, leading to therapeutic efforts to augment muscle growth by blocking GDF8 or ActRIIA/B. ActRIIA/B blockade approximately doubles the muscle increase of GDF8 blockade, and as ActRIIA/B responds to multiple other TGFβ-family members, this implies other ligands might also regulate muscle mass. Previously, we suggested that activin A (ActA) is the key second negative regulator acting via ActRIIA/B, as blockade of both GDF8 and ActA in mice/monkeys matches the muscle growth of ActRIIA/B blockade. Here, we extend these observations to humans in a two-part, randomized, placebo-controlled Phase 1 trial ( www.clinicaltrials.gov , NCT02943239) conducted at two sites in New Zealand. Eligible subjects included healthy postmenopausal females aged 45–70 years and males aged 35–60 years not intending to father children, with a body mass index of 18–32 kg/m 2 . Part I tested single-dose administration of anti-GDF8 alone, anti-ActA alone, several dose combinations of anti-GDF8 + anti-ActA, or placebo in healthy postmenopausal females; part II tested multiple-dose administration of anti-ActA alone or placebo in healthy postmenopausal females, combination anti-GDF8 + anti-ActA or placebo in healthy postmenopausal females, and anti-ActA alone or placebo in healthy males. The primary outcome measure was the incidence and severity of treatment-emergent adverse events through week 16 for the single-dose part of the study and through week 40 for the multiple-dose part of the study. Secondary endpoints included percent and absolute change in thigh muscle volume, percent and absolute change in total and regional body composition, pharmacokinetic profiles of the GDF8 and ActA mAbs in serum over time, changes in serum total GDF8 and total ActA levels over time, and the presence of anti-drug antibodies against the GDF8 mAb or the ActA mAb. Magnetic resonance imaging was used to quantitate changes in thigh muscle volume and dual x-ray absorptiometry was used to quantitate changes in regional body composition (total lean mass, appendicular lean body mass, android fat mass, and total fat mass). A total of 82 subjects were enrolled (48 in the single-dose part and 34 in the multiple-dose part of the study). Baseline demographic and clinical characteristics were generally balanced across the single- and multiple-dose parts of the study. Combining GDF8 and ActA blocking antibodies led to greater muscle growth than either antibody alone; increases in muscle were accompanied by reductions in fat. The observed clinical effects on muscle and fat paralleled mAb exposure in serum. The combination was generally well tolerated, and no subjects tested positive for anti-drug antibodies post-treatment. These results suggest that GDF8 and ActA are the dominant negative regulators of muscle mass in humans, and that combined blockade may be a promising therapeutic approach in muscle atrophy and obesity settings. GDF8 and activin A are the dominant negative regulators of muscle mass in animal models. This two-part, randomized, placebo-controlled Phase 1 trial suggests that GDF8 and activin A are also the dominant negative regulators of muscle mass in humans.

Background Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. Methods A 24 week, randomized, double‐blind, placebo‐controlled trial tested the impact of leucine‐enriched protein (LEU‐PRO), LEU‐PRO plus long‐chain n‐3 PUFA (LEU‐PRO+n‐3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within‐subject variation), the standard deviation of individual responses (SDR) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up‐and‐go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. Results The SDR was below the MCID for ALM (LEU‐PRO: −0.12 kg [90% CI: −0.38, 0.35], LEU‐PRO+n‐3: −0.32 kg [−0.45, 0.03], MCID: 0.21 kg), TUG (LEU‐PRO: 0.58 s [0.18, 0.80], LEU‐PRO+n‐3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU‐PRO: −0.38 mmol/L [−0.80, 0.25], LEU‐PRO+n‐3: −0.44 mmol/L [−0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU‐PRO (25 Nm [−29, 45]) and LEU‐PRO+n‐3 (23 Nm [−29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU‐PRO, LEU‐PRO+n‐3, and CON groups (P > 0.05). Baseline LC n‐3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU‐PRO or LEU‐PRO+n‐3 supplementation. Conclusions Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU‐PRO and LEU‐PRO+n‐3 supplementation in older adults at risk of sarcopenia.

Receptor activator of Nfkb ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. In turn a neutralizing Ab against RANKL, denosumab improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne's muscular dystrophy (mdx) and denervation-induce atrophy, but its role and mechanisms of action on muscle weakness in other conditions remains to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKL-Tg+), or lack Pparb and concomitantly develop sarcopenia (Pparb-/-). In women, denosumab over 3 years improved appendicular lean mass and handgrip strength compared to no treatment, whereas bisphosphonate did not. HuRANKL-Tg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decrease anti-myogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb-/-, OPG increased muscle volume and force, while also normalizing their insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusions, RANKL deteriorates, while its inhibitor improves, muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence denosumab could represent a novel therapeutic approach for sarcopenia.

Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle-specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age-related primary sarcopenia and outlines its pathogenesis and mechanisms.

Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation. The pathogenesis of sarcopenia is multifactorial and results from an imbalance between protein synthesis and breakdown. Nutritional, metabolic, and biochemical abnormalities seen in chronic liver disease alter whole body protein homeostasis. Hyperammonemia, increased autophagy, proteasomal activity, lower protein synthesis, and impaired mitochondrial function play an important role in muscle depletion in cirrhosis. Factors including cellular energy status, availability of metabolic substrates (e.g., branched-chain amino acids), alterations in the endocrine system (insulin resistance, circulating levels of insulin, insulin-like growth factor-1, corticosteroids, and testosterone), cytokines, myostatin, and exercise are involved in regulating muscle mass. A favored atrophy of type II fast-twitch glycolytic fibers seems to occur in patients with cirrhosis and sarcopenia. Identification of muscle biological abnormalities and underlying mechanisms is required to plan clinical trials to reverse sarcopenia through modulation of specific mechanisms. Accordingly, a combination of nutritional, physical, and pharmacological interventions might be necessary to reverse sarcopenia in cirrhosis. Moderate exercise should be combined with appropriate energy and protein intake, in accordance with clinical guidelines. Interventions with branched chain amino acids, testosterone, carnitine, or ammonia-lowering therapies should be considered individually. Various factors such as dose, type, duration of supplementations, etiology of cirrhosis, amount of dietary protein intake, and compliance with supplementation and exercise should be the focus of future large randomized controlled trials investigating both prevention and treatment of sarcopenia in this patient population.