Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in .

Age-dependent loss of body wall muscle function and impaired locomotion occur within 2 weeks in ; however, the underlying mechanism has not been fully elucidated. In humans, age-dependent loss of muscle function occurs at about 80 years of age and has been linked to dysfunction of ryanodine receptor (RyR)/intracellular calcium (Ca) release channels on the sarcoplasmic reticulum (SR). Mammalian skeletal muscle RyR1 channels undergo age-related remodeling due to oxidative overload, leading to loss of the stabilizing subunit calstabin1 (FKBP12) from the channel macromolecular complex. This destabilizes the closed state of the channel resulting in intracellular Ca leak, reduced muscle function, and impaired exercise capacity. We now show that the RyR homolog, , exhibits a remarkable degree of evolutionary conservation with mammalian RyR channels and similar age-dependent dysfunction. Like RyR1 in mammals, 68 encodes a protein that comprises a macromolecular complex which includes the calstabin1 homolog FKB-2 and is immunoreactive with antibodies raised against the RyR1 complex. Furthermore, as in aged mammals, is oxidized and depleted of FKB-2 in an age-dependent manner, resulting in 'leaky' channels, depleted SR Ca stores, reduced body wall muscle Ca transients, and age-dependent muscle weakness. FKB-2 (deficient worms exhibit reduced exercise capacity. Pharmacologically induced oxidization of and depletion of FKB-2 from the channel independently caused reduced body wall muscle Ca transients. Preventing FKB-2 depletion from the macromolecular complex using the Rycal drug S107 improved muscle Ca transients and function. Taken together, these data suggest that oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2-3 weeks in , suggesting that reduced antioxidant capacity may contribute to the differences in lifespan among species.