Abstract
Skeletal muscle contraction relies on both high-fidelity calcium (Ca2+) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca2+ 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 Ca2+ during excitation–contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca2+ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca2+ stores, store-operated Ca2+ entry (SOCE) provides an additional source of Ca2+ that originates from the extracellular space. In addition to Ca2+, skeletal muscle also requires ATP to both produce force and to replenish SR Ca2+ 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 Ca2+ handling, dysfunctional Ca2+-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.
Highlights
Dysfunctional or enhanced stromal-interacting molecule-1 (STIM1)/ORAI1-mediated store-operated Ca2+ entry (SOCE) is implicated in the pathogenesis of other muscle disorders including muscular dystrophy [59,60,61], malignant hyperthermia [62], and sarcopenia [63,64]. These findings demonstrate that a tight regulation of STIM1/ORAI1-dependent SOCE is critical for optimal muscle performance and that aberrant SOCE function contributes to muscle disease
Beside impaired EC coupling due to dihydropiridine receptors (DHPRs)/ryanodine receptor-1 (RyR1) uncoupling, reduced Ca2+ release units (CRUs) and CRU–mitochondrial association, altered mitochondria structure/function, and increased nitrosylation-dependent RyR1 Ca2+ leak, a reduction in STIM1/ORAI1-mediated SOCE activity is proposed tocontribute to age-dependent reduction in muscle specific force productionandincreasedsusceptibility to fatigue in aged muscle
Mitochondrial, and sarcoplasmic reticulum (SR) Ca2+ levels are needed, these studies suggest that increased oxidative stress signaling leading to alterations in Ca2+ homeostasis plays a significant role in certain forms of muscle atrophy and weakness
Summary
Left: EC uncoupling, due to the reduction of DHPR expression during aging or as the result of RyR1 loss-of-function point mutations (e.g., I4897T) linked to myopathies such as CCD, reduces electricallyevoked SR Ca2+ release that contributes to reduced muscle specific force production, disrupted mitochondrial structure/function, mitochondrial damage, and fiber structural alterations (e.g., formation of cores and myofibrillar disarray). Microtears promote non-specific influx of Ca2+ (and other ions) across the membrane followed by pathological myoplasmic Ca2+ overload that triggers an array of intracellular mechanisms that lead to myofiber degeneration and death including: dysregulation of cytosolicCa2+ homeostasis, mitochondrial Ca2+ overload/damage, increased mitochondrial ROS production and oxidative stress, and activation of the Ca2+dependent proteases [95,96] (Figure 1).
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