Altered Ca2+ Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease

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.

Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy

“…Consistent with this, treatment for 6 wk with an antioxidant ( N -acetylcysteine) significantly reduced the dystrophic phenotype of mdx mice ( Whitehead et al, 2008 ). A similar pathogenic role for altered Ca 2+ handling and excessive ROS production was demonstrated for other muscle disorders (malignant hyperthermia and central core disease) characterized by enhanced nitrosative/oxidative stress, RyR1 nitrosylation, SR Ca 2+ leak, and altered Ca 2+ homeostasis ( Durham et al, 2008 ; Lanner et al, 2012 ; Michelucci et al, 2015 ; Michelucci et al, 2017a ; Michelucci et al, 2017b ; Michelucci et al, 2021 ). However, whether functionally relevant ROS/RNS-dependent posttranslational modifications to proteins of the SOCE machinery (STIM1 and Orai1) occur in dystrophic muscle is unknown and certainly warrants future investigation.…”

H2O2/Ca2+/Zn2+ Complex Can Be Considered a “Collaborative Sensor” of the Mitochondrial Capacity?

“…The mitochondria of skeletal muscle fibers are arranged with three different distributions depending on the fiber phenotype examined [ 68 ]. In particular, in slow fibers, there is a group of mitochondria distributed in two longitudinal groups, one of which is subsarcolemmal, especially near the capillary network, evidently linked to oxidative phosphorylation and O 2 uptake, while a second category is arranged transversely, forming two rows on either side of the Z-line [ 69 ].…”

The benefits of physical activity on neuromuscular structure and function in old age

“…A recent article published in The Journal of Physiology by Soendenbroe et al (2022) aimed to determine the effects of lifelong physical activity on structural and functional changes in muscle. Three groups of male participants were compared, including young sedentary (n = 15; age range = 20-36 years), old sedentary (n = 15; age range = 68-82 years) and old physically active (n = 16; age range = 68-82 years) adults.…”

“…Moreover, it is essential that older and sedentary adults unaccustomed to producing high intensity efforts are fully familiarized with the prescribed physical activity, as large heterogeneity in neuromuscular structure and function, as well as motivation, decreases the reliability of the outcomes (Hunter et al, 2016). As highlighted by Soendenbroe et al (2022), the inclusion of males only is a limitation of their findings. This is a broad issue that is receiving increasing attention due to notable differences in female morphology and physiology when compared to males (Landen et al, 2022).…”