title: Molecular mechanisms of skeletal muscle atrophy in a mouse model of cerebral ischemia.
abstract: OBJECTIVE
  Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia.
  
  
  METHODS
  Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways).
  
  
  RESULTS
  Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated.
  
  
  CONCLUSIONS
  Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy.
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Marine Maud
authors.initials: MM
authors.lastname: Desgeorges
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Devillard
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Jérome
authors.initials: J
authors.lastname: Toutain
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Didier
authors.initials: D
authors.lastname: Divoux
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.).
authors.forename: Omar
authors.initials: O
authors.lastname: Touzani
authors.affiliation: From the Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France (M.M.D., X.D., J.C., D.G.F.); CNRS, UMR 6301 ISTCT, CERVOxy Group, GIP Cyceron, Caen, France (J.T., D.D., M.B., O.T.); CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.); and Université de Caen Basse Normandie, UMR 6301 ISTCT, Caen, France (J.T., D.D., M.B., O.T.). damien.freyssenet@univ-st-etienne.fr.
authors.forename: Damien Gilles
authors.initials: DG
authors.lastname: Freyssenet
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D009124:Muscle Proteins
keywords: Smad proteins; atrogenes; bone morphogenetic protein; myostatin; proteolysis; stroke