Researchers here provide a tour of better known pharmacological targets for the development of drugs to slow or potentially reverse loss of muscle mass and strength with age. The high bar to beat is the effects of resistance exercise, but there is likely merit in drugs that will enhance the improvements provided by resistance exercise, provided that they have a reasonable cost. A few common themes emerge in the targets. Many approaches produce a reduction in inflammation, as chronic inflammation is strongly implicated in loss of muscle tissue maintenance and tissue function, for example. Loss of stem cell activity and issues with neuromuscular junctions are also well studied in the context of muscle aging, and the research community has sought ways to address these issues. So far only limited progress has been made in bringing potential therapies to the clinic, but we might expect this to change over the next decade given the present strong interest in finding solutions to frailty, sarcopenia, and muscle loss produced by GLP-1 receptor agonists.
A progressive decline in muscle mass and strength presents a significant challenge for aging populations, underscoring the urgent need for innovative and diverse treatment strategies. While this review focuses on pharmacological options, structured physical exercise, particularly resistance and power training combined with sufficient protein intake, remains the most effective primary intervention for age-related muscle decline. Pharmacological methods should be viewed as supplementary or alternative options only when exercise is not possible or proves inadequate. Despite notable progress in understanding skeletal muscle degradation mechanisms, applying these findings to effective treatments requires further research and rigorous clinical testing. New therapies, including novel peptides, natural compounds, and multi-targeted pharmacological approaches, hold great promise to preserve muscle function and improve patient outcomes.
Looking ahead, priority biological targets include (i) modulation of the MSTN/activin A/GDF11 axis with careful cardiometabolic safety monitoring; (ii) stabilization of neuromuscular junctions (e.g., HDAC4-Gadd45a stress pathways; agrin/MuSK); (iii) restoration of mitochondrial quality control and bioenergetics (AMPK-SIRT1-PGC-1α signaling, mitophagy), with attention to preserving type II fibers; (iv) reduction of chronic low-grade inflammation (IL-6/TNF) and enhancement of insulin/IGF-1/Akt/mTOR signaling in sarcopenic phenotypes with metabolic comorbidities; and (v) strategies for extracellular matrix remodeling (balancing TGF-β/MMP activity) to improve the satellite cell niche.
Link: https://doi.org/10.3390/ph18091407
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