Premium
Chronic AMPK activation induces beneficial phenotypic adaptations in mdx mouse skeletal muscle
Author(s) -
Ljubicic Vladimir,
Lunde John A,
Boudreault Louise,
Khogali Shiemaa,
Burt Matthew,
Renaud JeanMarc,
Jasmin Bernard J
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1105.8
Subject(s) - duchenne muscular dystrophy , endocrinology , skeletal muscle , medicine , ampk , mdx mouse , utrophin , downregulation and upregulation , dystrophin , chemistry , biology , microbiology and biotechnology , protein kinase a , phosphorylation , biochemistry , gene
A therapeutic approach for Duchenne muscular dystrophy (DMD) is to upregulate utrophin levels in skeletal muscle in an effort to compensate for the lack of dystrophin. We have previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin upregulation, can attenuate the dystrophic pathology in mdx animals, the murine model of DMD. Indeed, treatment of mdx mice with the PPARδ activator GW501516 shifted muscle phenotype and ameliorated the disease pathology (Miura et al. Hum Mol Genet. 18:4640–49, 2009). Treatment of healthy mice with the AMPK activator AICAR enhances oxidative capacity and triggers a fast‐to‐slow fiber‐type transition. Our purpose was to evaluate the effects of chronic AICAR administration on muscle gene expression and the dystrophic pathology in mdx mice. AICAR mitigated muscle pseudo‐hypertrophy and attenuated central nucleation. Furthermore, we observed an elevation in mitochondrial enzyme activity, an increase in MHC IIa‐positive fibers, and slower twitch contraction kinetics in the EDL muscle. Utrophin and PGC‐1α proteins were augmented in response to AICAR, concomitant with a reduction in RIP140. Exercise increased utrophin A, PGC‐1α, and PPARδ mRNAs. This effect was attenuated with AICAR. Our data suggest that AICAR‐evoked muscle plasticity results in beneficial phenotypic adaptations in mdx mice. Supported by MDA (USA), CIHR and NSERC.