title: Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model.
abstract: Hypoxia induces a loss of skeletal muscle mass, but the signaling pathways and molecular mechanisms involved remain poorly understood. We hypothesized that hypoxia could impair skeletal muscle hypertrophy induced by functional overload (Ov). To test this hypothesis, plantaris muscles were overloaded during 5, 12, and 56 days in female rats exposed to hypobaric hypoxia (5,500 m), and then, we examined the responses of specific signaling pathways involved in protein synthesis (Akt/mTOR) and breakdown (atrogenes). Hypoxia minimized the Ov-induced hypertrophy at days 5 and 12 but did not affect the hypertrophic response measured at day 56. Hypoxia early reduced the phosphorylation levels of mTOR and its downstream targets P70(S6K) and rpS6, but it did not affect the phosphorylation levels of Akt and 4E-BP1, in Ov muscles. The role played by specific inhibitors of mTOR, such as AMPK and hypoxia-induced factors (i.e., REDD1 and BNIP-3) was studied. REDD1 protein levels were reduced by overload and were not affected by hypoxia in Ov muscles, whereas AMPK was not activated by hypoxia. Although hypoxia significantly increased BNIP-3 mRNA levels at day 5, protein levels remained unaffected. The mRNA levels of the two atrogenes MURF1 and MAFbx were early increased by hypoxia in Ov muscles. In conclusion, hypoxia induced a transient alteration of muscle growth in this hypertrophic model, at least partly due to a specific impairment of the mTOR/P70(S6K) pathway, independently of Akt, by an undefined mechanism, and increased transcript levels for MURF1 and MAFbx that could contribute to stimulate the proteasomal proteolysis.
authors.affiliation: Institut de Recherche Biomédicale des Armées, La Tronche, France. th.chaillou@gmail.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaillou
authors.forename: Nathalie
authors.initials: N
authors.lastname: Koulmann
authors.forename: Nadine
authors.initials: N
authors.lastname: Simler
authors.forename: Adélie
authors.initials: A
authors.lastname: Meunier
authors.forename: Bernard
authors.initials: B
authors.lastname: Serrurier
authors.forename: Rachel
authors.initials: R
authors.lastname: Chapot
authors.forename: Andre
authors.initials: A
authors.lastname: Peinnequin
authors.forename: Michèle
authors.initials: M
authors.lastname: Beaudry
authors.forename: Xavier
authors.initials: X
authors.lastname: Bigard
mesh_terms: D000818:Animals; D005260:Female; D006984:Hypertrophy; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D023421:Models, Animal; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D016474:Weight-Bearing / Q000502:physiology*
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases