Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy)

Hum Mol Genet. 2016 Jun 1;25(11):2194-2207. doi: 10.1093/hmg/ddw086. Epub 2016 Mar 22.


Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (CAPN3) gene. Our previous data suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3 knock-out mice (C3KO), Ca2+ release and Ca2+/calmodulin kinase II (CaMKII) signaling are attenuated. We 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, we compared transcriptomes of muscles from wild type (WT) and C3KO mice subjected to endurance exercise. In WT mice, exercise induces a gene signature that includes myofibrillar, mitochondrial and oxidative lipid metabolism genes, necessary for muscle adaptation. C3KO muscles fail to activate the same gene signature. Furthermore, in agreement with the aberrant transcriptional profile, we observe a commensurate functional defect in lipid metabolism whereby C3KO muscles fail to release fatty acids from stored triacylglycerol. In conjunction with the defects in oxidative metabolism, C3KO mice demonstrate 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, we elucidate 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 identify a novel mechanism of muscular dystrophy: a blunted transcriptional response to muscle loading resulting in chronic failure to adapt and remodel.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium Signaling
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics*
  • Calpain / biosynthesis
  • Calpain / genetics*
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Muscular Dystrophies, Limb-Girdle / physiopathology
  • Mutation
  • Oxidative Stress / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Transcriptional Activation / genetics
  • p38 Mitogen-Activated Protein Kinases / genetics


  • Muscle Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • p38 Mitogen-Activated Protein Kinases
  • Calpain
  • Capn3 protein, mouse

Supplementary concepts

  • Limb-girdle muscular dystrophy type 2A