Premium
Calpastatin overexpression in the skeletal muscle of mice prevents clenbuterol‐induced muscle hypertrophy and phenotypic shift
Author(s) -
Douillard Aymeric,
Galbes Olivier,
Begue Gwenaelle,
Rossano Bernadette,
Levin John,
Vernus Barbara,
Bonnieu Anne,
Candau Robin,
Py Guillaume
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05677.x
Subject(s) - calpastatin , calpain , ampk , skeletal muscle , clenbuterol , muscle hypertrophy , pi3k/akt/mtor pathway , medicine , endocrinology , camk , protein kinase a , phosphorylation , biology , chemistry , signal transduction , microbiology and biotechnology , autophosphorylation , biochemistry , enzyme
SummaryAccumulating evidence suggests that the calpain/calpastatin system is involved in skeletal muscle remodelling induced by β 2 ‐adrenoceptor agonist treatment. In addition to other pathways, the A kt/mammalian target of rapamycin ( mTOR ) pathway, controlling protein synthesis, and the calcium/calmodulin‐dependent protein kinase 2 ( CamK 2) and AMP ‐activated protein kinase ( AMPK ) pathways, recently identified as calpain substrates, could be relevant in β 2 ‐adrenoceptor agonist‐induced skeletal muscle remodelling. In the present study we investigated muscle hypertrophy and phenotypic shifts, as well as the molecular response of components of the A kt/ mTOR pathway (i.e. Akt, eukaryotic initiation factor 4E‐binding protein 1 ( 4E‐BP1 ), ribosomal protein S6 (rp S 6), CamK 2 and AMPK ), in response to calpastatin overexpression in the skeletal muscle of mice treated with 1 mg/kg per day clenbuterol for 21 days. Using gene electrotransfer of a calpastatin expression vector into the tibialis anterior of adult mice, we found that calpastatin overexpression attenuates muscle hypertrophy and phenotypic shifts induced by clenbuterol treatment. At the molecular level, calpastatin overexpression markedly decreased calpain activity, but was ineffective in altering the phosphorylation of A kt, 4E‐ BP 1 and rp S 6. In contrast, calpastatin overexpression increased the protein expression of both total AMPK and total CamK 2. In conclusion, the results support the contention that the calpain/calpastatin system plays a crucial role in skeletal muscle hypertrophy and phenotypic shifts under chronic clenbuterol treatment, with AMPK and CamK 2 probably playing a minor role. Moreover, the calpastatin‐induced inhibition of hypertrophy under clenbuterol treatment was not related to a decreased mTOR ‐dependent initiation of protein translation.