Altered Ca(2+) Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease

Skeletal muscle contraction relies on both high-fidelity calcium (Ca(2+)) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca(2+) release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca(2+) during excitation–contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca(2+) release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca(2+) stores, store-operated Ca(2+) entry (SOCE) provides an additional source of Ca(2+) that originates from the extracellular space. In addition to Ca(2+), skeletal muscle also requires ATP to both produce force and to replenish SR Ca(2+) stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca(2+) handling, dysfunctional Ca(2+)-dependent production of reactive oxygen/nitrogen species (ROS/RNS), and structural/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease.