C. Elegans as a Model to Study Ryanodine Receptor Function in Aging

Abstract

Though age-dependent deterioration of body wall muscle function has been characterized in C. elegans1, the underlying mechanism has not been fully characterized. We have identified age-dependent remodeling of the ryanodine receptor (RyR) homolog, UNC-68. We show for the first time that UNC-68 in young wild type nematodes is comprised of a macromolecular complex, which includes FKB-2, the homolog of the mammalian channel stabilizing subunit, Calstabin. Furthermore, UNC-68 is functionally regulated by FKB-2 in a manner similar to the regulation of mammalian RyR by Calstabin. UNC-68 is oxidized and depleted of FKB-2 in aged nematodes. We show for the first time that contraction-associated Ca2+ transients are reduced in an age-dependent manner in C. elegans, and age-dependent UNC-68 remodeling contributes to age-depended reduction in Ca2+ transients during body wall muscle contraction determined using a genetically encoded indicator. Re-associating FKB-2 with UNC-68 in aged nematodes using the RyR-stabilizing drug, S107, increased contraction-associated Ca2+ transients. Thus, RyR macromolecular complexes are highly conserved in C. elegans and present a useful model in which to study age-dependent remodeling of RyR channels. Moreover, RyR remodeling may play a role in nematode healthspan.