Targeting skeletal muscle wasting: Emerging therapeutics and translational challenges.

Abstract

Skeletal muscle wasting is a multifactorial syndrome that contributes to weakness, reduced physical function, loss of independence, and poor clinical outcomes across aging, cancer, obesity, heart failure, disuse, and rare neuromuscular diseases. Although major advances have illuminated much of the molecular signaling for skeletal muscle, effective pharmacologic therapy remains extremely limited. This narrative review examines current and emerging drug-development strategies for muscle wasting with an emphasis on mechanistic rationale, translational evidence, and the barriers that continue to impede clinical success. The focus is on four major therapeutic areas: myostatin/activin pathway inhibition, selective androgen receptor modulators, ghrelin-related appetite-directed therapies, and mitochondria-targeted approaches. Across these classes, preclinical studies have shown that pharmacologic manipulation of anabolic or catabolic signaling, energy intake, and mitochondrial function can preserve or increase muscle mass and, in some settings, improve survival or selected functional measures. However, clinical translation has been inconsistent. A recurring theme is that favorable effects on muscle mass or muscle size do not translate into improvements in strength, mobility, fatigue, or patient-centered outcomes. Additional barriers include disease heterogeneity, limitations of preclinical models, muscle maintenance after therapy, safety concerns, regulatory demands for clinically meaningful endpoints, as well as the complexity of rare-disease development. Future progress will depend on biomarker-guided and phenotype-enriched trial design, multimodal interventions, and outcome measures that capture muscle function.