2026/01/01 by Eva Tamayo-Torres, Fernando Millán-Domingo, Javier Comes-Fayos +1 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Muscle Physiology and Disorders #Nutrition and Health in Aging #Exercise and Physiological Responses
paper · doi:10.1530/rem-25-0020
openalex publication_date 2026/01/01 · openalex created_date 2026/01/14 · openalex updated_date 2026/07/08
Aging of skeletal muscle is characterized by a progressive loss of mass and strength, driven by structural alterations, including a reduction in fiber cross-sectional area, motoneuron degeneration, and a shift toward slower fiber phenotypes. These changes underlie sarcopenia, a major contributor to frailty and loss of independence. Central biological mechanisms underlying this process include mitochondrial dysfunction and redox imbalance. Reactive oxygen species (ROS), once viewed as damaging by-products, are now recognized as dual regulators: at moderate levels, they promote adaptive responses (oxidative eustress), whereas in excess, they drive oxidative distress and molecular damage. This framework helps explain why transient ROS production during exercise triggers beneficial processes, such as mitochondrial biogenesis, antioxidant upregulation, and contractile remodeling, thereby extending functional health span. A remarkable cellular and nuclear heterogeneity defines skeletal muscle. Recent single-cell and single-nucleus atlases have revealed specialized nuclear subpopulations and dynamic changes that occur with age. Type II fiber myonuclei, for example, are particularly vulnerable to aging, exhibiting loss of ENOX1+ subsets that support glycolytic metabolism and redox resilience. In parallel, shifts in resident non-myogenic cells, including fibro-adipogenic progenitors, endothelial cells, immune cells, and Schwann cells, reinforce a pro-inflammatory and fibrotic microenvironment. These alterations compromise regenerative potential, exacerbate metabolic decline, and accelerate fiber-type-specific atrophy in aged skeletal muscle. Skeletal muscle exemplifies tissue-level complexity, in which disruption of a single cellular component propagates across the entire network. Exercise training emerges as the most potent non-pharmacological intervention for restoring redox balance, improving systemic communication, and counteracting age- and disease-related dysregulation.