Aging is a universal biological process signified by a time-dependent decline in physiological activity, driven by molecular and cellular damage, leading to greater susceptibility to diseases and fatal outcomes. Impaired proteostasis is a key aspect of cellular aging in which the cells become less efficient at folding, repairing, and recycling proteins, consequently inducing accumulation of damaged and aggregation-prone proteins. The onset of muscle loss is driven by a reduction in protein synthesis, heightened activation of proteolytic pathways, and elevated ER stress factors, collectively contributing to functional decline and increased vulnerability with aging. Muscle atrophy, whether age-related or driven by chronic illness, represents a major role in defective health, impacting both quality of life and survival. This review explores the intricate and multidimensional nature of proteostasis network regulating protein quality control across skeletal muscles. We examined how the malfunction of components within proteostasis networks during aging contributes to the induction, progression, and chronicity of common age-related muscle wasting. Experimental and clinical studies exploring potential therapeutic strategies for better proteostasis in muscle wasting have been discussed. In this review, we emphasized the increasing demand for effective therapeutic interventions that can slow down or mitigate age-related deterioration in muscle physiology and sustain mobility and quality of life in the elderly. We analyzed the roles of ubiquitin proteasome system, autophagy lysosomal pathway, and unfolded protein response in muscle wasting, highlighting protein loss from synthesis-degradation imbalance as a major driver of muscle atrophy under catabolic conditions. This review outlines key findings with emerging insights to help drive the development of targeted therapies against muscle wasting. Looking ahead, emerging approaches such as PROTACs, extracellular vesicle-based therapies, and artificial intelligence-driven predictive models hold promise for advancing precision interventions in muscle wasting research.
