Defective mitochondrial quality control in the aging of skeletal muscle

Abstract

Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation–contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.