Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling

FEBS J. 2009 Feb;276(3):669-84. doi: 10.1111/j.1742-4658.2008.06814.x.

Abstract

In an attempt to identify potential therapeutic targets for the correction of muscle wasting, the gene expression of several pivotal proteins involved in protein metabolism was investigated in experimental atrophy induced by transient or definitive denervation, as well as in four animal models of muscular dystrophies (deficient for calpain 3, dysferlin, alpha-sarcoglycan and dystrophin, respectively). The results showed that: (a) the components of the ubiquitin-proteasome pathway are upregulated during the very early phases of atrophy but do not greatly increase in the muscular dystrophy models; (b) forkhead box protein O1 mRNA expression is augmented in the muscles of a limb girdle muscular dystrophy 2A murine model; and (c) the expression of cardiac ankyrin repeat protein (CARP), a regulator of transcription factors, appears to be persistently upregulated in every condition, suggesting that CARP could be a hub protein participating in common pathological molecular pathway(s). Interestingly, the mRNA level of a cell cycle inhibitor known to be upregulated by CARP in other tissues, p21(WAF1/CIP1), is consistently increased whenever CARP is upregulated. CARP overexpression in muscle fibres fails to affect their calibre, indicating that CARP per se cannot initiate atrophy. However, a switch towards fast-twitch fibres is observed, suggesting that CARP plays a role in skeletal muscle plasticity. The observation that p21(WAF1/CIP1) is upregulated, put in perspective with the effects of CARP on the fibre type, fits well with the idea that the mechanisms at stake might be required to oppose muscle remodelling in skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Calpain / deficiency
  • Calpain / genetics
  • Calpain / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease Models, Animal
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Male
  • Mice
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology*
  • Muscular Dystrophies / genetics
  • Muscular Dystrophies / metabolism*
  • Muscular Dystrophies / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Up-Regulation

Substances

  • Ankrd1 protein, mouse
  • Biomarkers
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Muscle Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Calpain
  • Capn3 protein, mouse
  • Proteasome Endopeptidase Complex