title: Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy).
abstract: 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.
authors.affiliation: Department of Neurology, David Geffen School of Medicine Center for Duchenne Muscular Dystrophy ikramero@ucla.edu mspencer@mednet.ucla.edu.
authors.forename: Irina
authors.initials: I
authors.lastname: Kramerova
authors.affiliation: Department of Neurology, David Geffen School of Medicine Center for Duchenne Muscular Dystrophy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ermolova
authors.affiliation: Center for Duchenne Muscular Dystrophy Department of Human Genetics, David Geffen School of Medicine.
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.affiliation: Center for Duchenne Muscular Dystrophy Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hevener
authors.affiliation: Department of Medicine Department of Pharmacology, University of California, San Diego, CA 92093, USA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA 92093, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Armando
authors.affiliation: Department Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas, TX 75231, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Haller
authors.affiliation: Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas, TX 75231, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Romain
authors.affiliation: Center for Duchenne Muscular Dystrophy Department of Human Genetics, David Geffen School of Medicine.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Neurology, David Geffen School of Medicine Center for Duchenne Muscular Dystrophy ikramero@ucla.edu mspencer@mednet.ucla.edu.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis / Q000235:genetics*; D002154:Calpain / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; D002154:Calpain; C491373:Capn3 protein, mouse