Recovery of the Compromised Ca 2+ Spark Signaling in Aged Skeletal Muscle Through Restoration of MG29

Abstract

Sarcopenia is a degenerative loss of skeletal muscle function associated with aging. Our previous results identify reduced MG29 expression in aged skeletal muscle, and mirroring phenotypes of the young MG29 knockout and aged wild type muscles in that both show reduced Ca2+ spark response to osmotic-stress. Thus, compromised intracellular Ca2+ homeostasis due to reduced MG29 expression may be one of the underling mechanisms for aging-related skeletal muscle dysfunction. Here we explored the effects of MG29 rescue on Ca2+ spark signaling in aged skeletal muscle. Electroporation-based method was used to introduce MG29 into flexor digitorum brevis (FDB) muscle and adeno-associated virus (AAV)-based method was used to deliver MG29 gene into the hindlimb of the living mice. Confocal microscopic imaging revealed increased Ca2+ spark events in aged FDB muscle following transient overexpression of MG29. These Ca2+ sparks showed plastic response to osmotic stresses, similar to those observed in the young wild type muscle. 2-3 weeks following AAV-mediated delivery of MG29, the aged skeletal muscle showed only marginal increase in contractile force as compared to the contralateral controls. Our data suggest that transient restoration of MG29 expression in aged muscle has beneficial effects on improvement of intracellular Ca2+ signaling. Since MG29 is involved in maintenance of the transverse-tubule network, restoration of contractile force in aged muscle may require sustained elevation of MG29 to allow for remodeling of the disrupted membrane network.