Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (Capn3) gene. Previous data from this group suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3knock-out mice (C3KO), Ca2+release and Ca2+/calmodulin kinase II (CaMKII) signaling are attenuated. It was hypothesized that calpainopathy may result from a failure to transmit loading-induced Ca2+-mediated signals, necessary to up-regulate expression of muscle adaptation genes. To test this hypothesis, the authors compared transcriptomes of muscles from wild-type and C3KO mice subjected to endurance exercise. In wild-type mice, exercise induced a gene signature that includes myofibrillar, mitochondrial and oxidative lipid metabolism genes, necessary for muscle adaptation. C3KO muscles failed to activate the same gene signature. Furthermore, in agreement with the aberrant transcriptional profile, they observed a commensurate functional defect in lipid metabolism whereby C3KO muscles failed to release fatty acids from stored triacylglycerol. In conjunction with the defects in oxidative metabolism, C3KO mice demonstrated reduced exercise endurance. Failure to up-regulate genes in C3KO muscles is due, in part, to decreased levels of PGC1α, a transcriptional co-regulator that orchestrates the muscle adaptation response. Destabilization of PGC1α is attributable to decreased p38 MAPK activation via diminished CaMKII signaling. Thus, the authors have elucidated a pathway downstream of Ca2+-mediated CaMKII activation that is dysfunctional in C3KO mice, leading to reduced transcription of genes involved in muscle adaptation. These studies have identified a novel mechanism of muscular dystrophy: a blunted transcriptional response to muscle loading resulting in chronic failure to adapt and remodel.
