Objective The purpose of this study was to perform a systematic review to assess the short-, middle- and long-term consequences of sarcopenia. Methods Prospective studies assessing the consequences of sarcopenia were searched across different electronic databases (MEDLINE, EMBASE, EBM Reviews, Cochrane Database of Systematic Reviews, EBM Reviews ACP Journal Club, EBM Reviews DARE and AMED). Only studies that used the definition of the European Working Group on Sarcopenia in Older People to diagnose sarcopenia were included. Study selection and data extraction were performed by two independent reviewers. For outcomes reported by three or more studies, a meta-analysis was performed. The study results are expressed as odds ratios (OR) with 95% CI. Results Of the 772 references identified through the database search, 17 were included in this systematic review. The number of participants in the included studies ranged from 99 to 6658, and the duration of follow-up varied from 3 months to 9.8 years. Eleven out of 12 studies assessed the impact of sarcopenia on mortality. The results showed a higher rate of mortality among sarcopenic subjects (pooled OR of 3.596 (95% CI 2.96–4.37)). The effect was higher in people aged 79 years or older compared with younger subjects (p = 0.02). Sarcopenia is also associated with functional decline (pooled OR of 6 studies 3.03 (95% CI 1.80–5.12)), a higher rate of falls (2/2 studies found a significant association) and a higher incidence of hospitalizations (1/1 study). The impact of sarcopenia on the incidence of fractures and the length of hospital stay was less clear (only 1/2 studies showed an association for both outcomes). Conclusion Sarcopenia is associated with several harmful outcomes, making this geriatric syndrome a real public health burden.

Health outcomes of sarcopenia: a systematic review and meta-analysis.

BACKGROUND Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing-related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. METHODS A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non-sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty-two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre-intensive and post-intensive lifestyle interventions, were measured. RESULTS The sarcopenic group was significantly older (72.05 ± 6.54 years; P  11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6-fold and 14.3-fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4-fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF-α, IL-18, insulin, and adiponectin (all P < 0.05). CONCLUSIONS High levels of the inflammatory cytokines TWEAK and TNF-α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could significantly improve muscle mass, reduce inflammation, and restore metabolic hormone levels in sarcopenic patients. This trial was registered at clinicaltrials.gov as NCT02873676.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcsm.12417

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention

The continuous population increase of older adults with metabolic diseases may contribute to increased prevalence of sarcopenia and obesity and requires advocacy of optimal nutrition treatments to combat their deleterious outcomes. Sarcopenic obesity, characterized by age-induced skeletal-muscle atrophy and increased adiposity, may accelerate functional decline and increase the risk of disability and mortality. In this review, we explore the influence of dietary protein on the gut microbiome and its impact on sarcopenia and obesity. Given the associations between red meat proteins and altered gut microbiota, a combination of plant and animal-based proteins are deemed favorable for gut microbiota eubiosis and muscle-protein synthesis. Additionally, high-protein diets with elevated essential amino-acid concentrations, alongside increased dietary fiber intake, may promote gut microbiota eubiosis, given the metabolic effects derived from short-chain fatty-acid and branched-chain fatty-acid production. In conclusion, a greater abundance of specific gut bacteria associated with increased satiation, protein synthesis, and overall metabolic health may be driven by protein and fiber consumption. This could counteract the development of sarcopenia and obesity and, therefore, represent a novel approach for dietary recommendations based on the gut microbiota profile. However, more human trials utilizing advanced metabolomic techniques to investigate the microbiome and its relationship with macronutrient intake, especially protein, are warranted.

/pdf/impact-of-protein-intake-in-older-adults-with-sarcopenia-and-3r7qs8i87i.pdf

Impact of Protein Intake in Older Adults with Sarcopenia and Obesity: A Gut Microbiota Perspective.

Selection and identification of a novel ssDNA aptamer targeting human skeletal muscle

Aging and osteoarthritis (OA) are associated with a high risk of muscle mass loss, which can lead to physical disability. This study investigated the effectiveness of protein supplementation combined with exercise training (PS + ET) in improving muscle mass and functional outcomes in older adults with lower-limb OA. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) on the effectiveness of PS + ET in older adults with hip or knee OA. Meta-analysis and risk of bias assessment of the included RCTs were conducted. Six RCTs were included in this systemic review; they had a median (range/total) Physiotherapy Evidence Database (PEDro) score of 7 (6-9) out of 10, respectively. Five RCTs that enrolled patients who underwent total joint replacement were included in this meta-analysis. The PS + ET group exhibited significant improvements in muscle mass (standard mean difference [SMD] = 1.13, p < 0.00001), pain (SMD = 1.36, p < 0.00001), and muscle strength (SMD = 0.44, p = 0.04). Our findings suggest that PS + ET improves muscle mass, muscle strength, and functional outcomes and reduces pain in older adults with lower-limb OA, particularly in those who have undergone total joint replacement.

/pdf/effects-of-protein-supplementation-combined-with-exercise-rhm7qmtcne.pdf

Effects of Protein Supplementation Combined with Exercise Training on Muscle Mass and Function in Older Adults with Lower-Extremity Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Trials

Sarcopenia is characterized by loss of muscle and reduction in muscle strength that contributes to higher mortality rate and increased incidence of fall and hospitalization in the elderly. Mitochondria dysfunction and age-associated inflammation in muscle are two of the main attributors to sarcopenia progression. Recent clinical trials on sarcopenia therapies such as physical exercise, nutraceutical, and pharmaceutical interventions have revealed that exercise is the only effective strategy shown to alleviate sarcopenia. Unlike nutraceutical and pharmaceutical interventions that showed controversial results in sarcopenia alleviation, exercise was found to restore mitochondria homeostasis and dampen inflammatory responses via a complex exchange of myokines and osteokines signalling between muscle and bone. However, as exercise have limited benefit to immobile patients, the use of stem cells and their secretome are being suggested to be novel therapeutics that can be catered to a larger patient population owing to their mitochondria restoration effects and immune modulatory abilities. As such, we reviewed the potential pros and cons associated with various stem cell types/secretome in sarcopenia treatment and the regulatory and production barriers that need to be overcome to translate such novel therapeutic agents into bedside application. Translational potential: This review summarizes the causes underlying sarcopenia from the perspective of mitochondria dysfunction and age-associated inflammation, and the progress of clinical trials for the treatment of sarcopenia. We also propose therapeutic potential of stem cell therapy and bioactive secretome for sarcopenia.

Sarcopenia: Current treatments and new regenerative therapeutic approaches

Mitochondrial transfer is a spontaneous process to restore damaged cells in various pathological conditions. The transfer of mitochondria to cell therapy products before their administration can enhance therapeutic outcomes. However, the low efficiency of previously reported methods limits their clinical application. Here, we developed a droplet microfluidics–based mitochondrial transfer technique that can achieve high-efficiency and high-throughput quantitative mitochondrial transfer to single cells. Because mitochondria are essential for muscles, myoblast cells and a muscle injury model were used as a proof-of-concept model to evaluate the proposed technique. In vitro and in vivo experiments demonstrated that C2C12 cells with 31 transferred mitochondria had significant improvements in cellular functions compared to those with 0, 8, and 14 transferred mitochondria and also had better therapeutic effects on muscle regeneration. The proposed technique can considerably promote the clinical application of mitochondrial transfer, with optimized cell function improvements, for the cell therapy of mitochondria-related diseases.

High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration

Background: Loss of skeletal muscle mass and function is one of the major musculoskeletal health problems in the aging population. Recent studies have demonstrated differential proteomic profiles at different fetal stages, which might be associated with muscle growth and development. We hypothesized that extract derived from fetal muscle tissues at the stage of hypertrophy could ameliorate the loss of muscle mass and strength in aged mice. Methods: To allow sufficient raw materials for investigation, skeletal muscle extract from fetal sheep at week 16 of gestation and maternal tissue were used in the present study. iTRAQ (isobaric tags for relative and absolute quantitation) and KEGG pathway analyses identified differentially expressed proteins in fetal sheep muscle extract vs. adult sheep muscle extract. Effects of FSME and ASME on human myoblast proliferation were studied. To examine the effect of FSME in vivo, C57BL/6 male mice at 20 months of age were subjected to intramuscular administration of FSME or vehicle control for 8 weeks. A grip strength test and ex vivo muscle force frequency test were conducted. Finally, serum samples were collected for multiplex analysis to determine potential changes in immunological cytokines upon FSME injection. Results: Compared with ASME, 697 and 412 peptides were upregulated and downregulated, respectively, in FSME, as indicated by iTRAQ analysis. These peptides were highly related to muscle development, function, and differentiation from GO enrichment analysis. FSME promoted cell proliferation of myoblast cells (+300%, p < 0.01) without causing significant cytotoxicity at the tested concentration range compared with ASME. After 8 weeks of FSME treatment, the percentage of lean mass (+10%, p < 0.05), grip strength (+50%, p < 0.01), and ability in fatigue resistance were significantly higher than those of the control group. Isometric forces stimulated by different frequencies were higher in the control group. Histologically, the control group showed a larger cross-sectional area (+20%, p < 0.01) than the FSME group. The multiplex assay indicated that FSME treatment did not lead to an elevated circulatory level of inflammatory cytokines. Of note, after FSME treatment, we observed a significant drop in the circulating level of IL-12 (p40) from 90.8 ± 48.3 pg/ml to 82.65 ± 4.4 pg/ml, G-CSF from 23476 ± 8341.9 pg/ml to 28.35 ± 24.2 pg/ml, KC from 97.09 ± 21.2 pg/ml to 29.2 ± 7.2 pg/ml, and RANTES from 325.4 ± 17.3 pg/ml to 49.96 ± 32.1 pg/ml. Conclusion: This is the first study demonstrating the beneficial effect of fetal muscle extract on muscle health in aged mice. Further analysis of the active ingredients of the extract will shed light on the development of a novel treatment for sarcopenia.

https://www.frontiersin.org/articles/10.3389/fphys.2022.816774/pdf

Tszlam Yiu

Papers

Sarcopenia: Current treatments and new regenerative therapeutic approaches

High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration

Fetal muscle extract improves muscle function and performance in aged mice