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.

Oxidative stress resulting from decreased antioxidant protection and increased reactive oxygen and nitrogen species (RONS) production may contribute to muscle mass loss and dysfunction during aging. Curcumin is a phenolic compound shown to upregulate antioxidant defenses and directly quench RONS in vivo. This study determined the impact of prolonged dietary curcumin exposure on muscle mass and function of aged rats. Thirty-two-month-old male F344xBN rats were provided a diet with or without 0.2% curcumin for 4 months. The groups included: ad libitum control (CON; n = 18); 0.2% curcumin (CUR; n = 18); and pair-fed (PAIR; n = 18) rats. CUR rats showed lower food intake compared to CON, making PAIR a suitable comparison group. CUR rats displayed larger plantaris mass and force production (vs. PAIR). Nuclear fraction levels of nuclear factor erythroid-2 related-factor-2 were greater, and oxidative macromolecule damage was lower in CUR (vs. PAIR). There were no significant differences in measures of antioxidant status between any of the groups. No difference in any measure was observed between CUR and CON rats. Thus, consumption of curcumin coupled with reduced food intake imparted beneficial effects on aged skeletal muscle. The benefit of curcumin on aging skeletal muscle should be explored further.

Excessive iron loading may cause skeletal muscle atrophy and weakness because of its free radical generating properties. To determine whether a clinically relevant degree of iron loading impairs skeletal muscle function, young male mice received injections of iron dextran (4 mg iron/200 µl) or 2 mM d-glucose (control) 5 days/week for 2 weeks ( n = 10/group). Systemic iron loading induced an approximate fourfold increase in the skeletal muscle nonheme iron concentration. Soleus specific tension (1, 30–250 Hz) was lower among iron-loaded animals compared with controls despite similar body mass and muscle mass. Soleus lipid peroxidation (4-hydroxynonenal adducts) and protein oxidation (protein carbonyls) levels were similar between groups. In gastrocnemius muscle, reduced glutathione (GSH) and glutathione peroxidase activity were similar but glutathione disulfide (GSSG) and the GSSG/GSH ratio were greater in iron-loaded muscle. A greater protein expression level of endogenous thiol antioxidant thioredoxin (TRX) was observed among iron-loaded muscle whereas its endogenous inhibitor thioredoxin-interacting protein (TXNip) and the TRX/TXNip ratio were similar. Glutaredoxin2, a thiol-disulfide oxidoreductase activated by GSSG-induced destabilization of its iron-sulfur [2Fe-2S] cluster, was lower following iron loading. Additionally, protein levels of α-actinin and αII-spectrin at 240 kDa were lower in the iron-loaded group. Ryanodine receptor stabilizing subunit calstabin1 was also lower following iron loading. In summary, the contractile dysfunction that resulted from moderate iron loading may be mediated by a disturbance in the muscle redox balance and from changes arising from an increased proteolytic response and aberrant sarcoplasmic reticulum Ca²⁺ release. NEW & NOTEWORTHY Although severe iron loading is known to cause muscle oxidative stress and dysfunction, the effects of a moderate degree of systemic iron loading on muscle contractile function and biochemical responses remain unclear. This study demonstrates that a pathophysiological elevation in the skeletal muscle iron load leads to force deficits that coincide with impaired redox status, structural integrity, and lower ryanodine receptor-associated calstabin1 in the absence of muscle mass changes or oxidative damage.

Aging skeletal muscle displays an altered iron status that may promote oxidative stress and sarcopenia. A diet containing low iron (LI) could reduce muscle iron status and attenuate age-related muscle atrophy. Supplemental branched-chain amino acids (BCAA) may also alleviate sarcopenia by promoting muscle protein synthesis and iron status improvement. This study examined individual and combined effects of LI and BCAA diets on anabolic signaling and iron status in skeletal muscle of aging rats. Twenty-nine-month-old male Fisher 344 × Brown Norway rats consumed the following control-base diets: control + regular iron (35 mg iron/kg) (CR; n = 11); control + LI (∼6 mg iron/kg) (CL; n = 11); 2×BCAA + regular iron (BR; n = 10); and 2×BCAA + LI (BL; n = 12) for 12 weeks. Although LI and/or 2×BCAA did not affect plantaris muscle mass, 2×BCAA groups showed lower muscle iron content than did CR and CL groups (P < 0.05). p70 ribosomal protein S6 kinase phosphorylation was greater in 2×BCAA and LI animals compared with CR animals (P < 0.05). Interactions between IRON and BCAA were observed for proteins indicative of mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1 alpha) and oxidative capacity (cytochrome c oxidase subunit 2 and citrate synthase) (P < 0.05) wherein the combined diet (BL) negated potential benefits of individual diets. Antioxidant capacity, superoxide dismutase activity, and oxidative injury (3-nitrotyrosine, protein carbonyls, and 4-hydroxynonenal) were similar between groups. In conclusion, 12 weeks of LI and 2×BCAA diets showed significant impacts on increasing anabolic signaling as well as ameliorating iron status; however, these interventions did not affect muscle mass.

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed straight-tubules observed in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. Here, we assessed the therapeutic potential of endurance exercise in the form of voluntary wheel running (VWR) in mitigating TAs and muscle weakness in Orai1G100S/+ (GS) mice harboring a gain-of-function mutation in the ORAI1 pore. Six months of VWR exercise significantly increased specific force production, upregulated biosynthetic and protein translation pathways, and normalized both mitochondrial protein expression and morphology in the soleus of GS mice. VWR also restored Ca2+ store content, reduced the incidence of TAs, and normalized pathways involving the formation of supramolecular complexes in fast twitch muscles of GS mice. In summary, sustained voluntary endurance exercise improved multiple skeletal muscle phenotypes observed in the GS mouse model of TAM.