GLYCATION AND SKELETAL MUSCLE DYSFUNCTION IN DIABETES: INSIGHTS INTO MOLECULAR PATHWAYS AND THERAPEUTIC STRATEGIES

Skeletal muscle, accounting for nearly 40% of body weight, plays a pivotal role not only in locomotion but also in metabolic and endocrine regulation. Muscle health and adaptability depend on progenitor cells, including satellite and non-satellite populations, which are compromised in disease states such as diabetes mellitus. Aging further exacerbates muscle decline, with sarcopenia contributing to frailty, disability, and mortality. A key molecular mechanism underlying skeletal muscle dysfunction is non-enzymatic glycation, leading to the formation of advanced glycation end-products (AGEs). These accumulate in structural proteins such as collagen and plasma proteins like albumin, disrupting their biological functions, impairing regeneration, and stiffening the extracellular matrix. AGEs also engage the receptor for advanced glycation end-products (RAGE), triggering oxidative stress, mitochondrial dysfunction, and inflammatory pathways, with implications for cancer, insulin resistance, and neuro-muscular degeneration. Therapeutic interventions targeting AGE formation and signaling include aminoguanidine, pyridoxamine, benfotiamine, statins, thiazolidinediones, and emerging agents like alagebrium and soluble RAGE. Natural antioxidants such as phenolic acids show potential, though their effects remain inconsistent. Clinical translation of anti-AGE strategies emphasizes patient-specific molecular profiles, precision medicine, and the integration of biomarkers to optimize treatment outcomes. This review underscores the importance of understanding glycation-mediated muscle dysfunction, highlights novel therapeutic strategies, and explores translational opportunities to bridge basic science with clinical practice, ultimately aiming to improve muscle health and reduce age- and diabetes-related complications.