Down-regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle.
Myostatin, a member of the TGF-beta family, has been identified as a master regulator of embryonic myogenesis and early postnatal skeletal muscle growth. However, cumulative evidence also suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression and that myostatin may contribute to muscle mass loss in adulthood. Two major branches of the Akt pathway are relevant for the regulation of skeletal muscle mass, the Akt/mammalian target of rapamycin (mTOR) pathway, which controls protein synthesis, and the Akt/forkhead box O (FOXO) pathway, which controls protein degradation. Here, we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt/mTOR signaling pathway. Electrotransfer of a myostatin expression vector into the tibialis anterior muscle of Sprague Dawley male rats increased myostatin protein level and decreased skeletal muscle mass 7 d after gene electrotransfer. Using RT-PCR and immunoblot analyses, we showed that myostatin overexpression was ineffective to alter the ubiquitin-proteasome pathway. By contrast, myostatin acted as a negative regulator of Akt/mTOR pathway. This was supported by data showing that the phosphorylation of Akt on Thr308, tuberous sclerosis complex 2 on Thr1462, ribosomal protein S6 on Ser235/236, and 4E-BP1 on Thr37/46 was attenuated 7 d after myostatin gene electrotransfer. The data support the conclusion that Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.
Amirouche
Adel
A
Pôle de Recherche et d'Enseignement Supérieur Université de Lyon, Université Jean Monnet, Laboratoire de Physiologie de l'Exercice, Equipe d'accueil, Saint Etienne, France.
Durieux
Anne-Cécile
AC
Banzet
Sébastien
S
Koulmann
Nathalie
N
Bonnefoy
Régis
R
Mouret
Catherine
C
Bigard
Xavier
X
Peinnequin
André
A
Freyssenet
Damien
D
D000818:Animals; D001284:Atrophy; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D015536:Down-Regulation; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D055435:Myostatin / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases
D017931:DNA Primers; D055435:Myostatin; D004247:DNA; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases