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Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism

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Przygodda, Franciele ; Manfredi, Leandro Henrique ; Machado, Juliano ; Goncalves, Dawit A. P. ; Zanon, Neusa M. ; Bonagamba, Leni G. H. ; Machado, Benedito H. ; Kettelhut, Isis C. ; Navegantes, Luiz C. C.
Número total de Autores: 9
Tipo de documento: Artigo Científico
Fonte: Journal of Applied Physiology; v. 122, n. 5, p. 1114-1124, MAY 2017.
Citações Web of Science: 2

Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermittent hypoxia on skeletal muscle protein metabolism remain unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6% O-2 for 40 s at 9-min intervals). Animals were euthanized, and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turnover. AIH increased plasma levels of corticosterone and induced insulin resistance as estimated by the insulin tolerance test and lower rates of muscle glucose oxidation and the HOMA index. In both soleus and EDL muscles, rates of overall proteolysis increased after AIH. This rise was accompanied by an increased proteolytic activities of the ubiquitin(Ub)-proteasome system (UPS) and lysosomal and Ca2+ -dependent pathways. Furthermore, AIH increased Ub-protein conjugates and gene expression of atrogin-1 and MuRF-1, two key Ub-protein ligases involved in muscle atrophy. In parallel, AIH increased the mRNA expression of the autophagy-related genes LC3b and GABARAPl1. In vitro rates of protein synthesis in skeletal muscles did not differ between AIH and control rats. ADX completely blocked the insulin resistance in hypoxic rats and the AIH-induced activation of proteolytic pathways and atrogene expression in both soleus and EDL muscles. These results demonstrate that AIH induces insulin resistance in association with activation of the UPS, the autophagic-lysosomal process, and Ca2+ dependent proteolysis through a glucocorticoid-dependent mechanism. NEW \& NOTEWORTHY Since hypoxia is a condition in which the body is deprived of adequate oxygen supply and muscle wasting is induced, the present work provides evidence linking hypoxia to proteolysis through a glucocorticoid-dependent mechanism. We show that the activation of proteolytic pathways, atrophy-related genes, and insulin resistance in rats exposed to acute intermittent hypoxia was abolished by surgical removal of adrenal gland. This finding will be helpful for understanding of the muscle wasting in hypoxemic conditions. (AU)

Processo FAPESP: 08/06694-6 - Controle neural do metabolismo de proteínas
Beneficiário:Isis Do Carmo Kettelhut
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/18861-0 - A hiperacetilação de FOXO como um mecanismo de supressão do programa gênico atrófico pela sinalização adrenérgica beta2 em músculos esqueléticos de roedores
Beneficiário:Dawit Albieiro Pinheiro Gonçalves
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 15/21112-7 - Controle da massa muscular pela via de sinalização do AMPc
Beneficiário:Juliano Machado
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 12/24524-6 - Controle da massa muscular pela via de sinalização do AMPc
Beneficiário:Isis Do Carmo Kettelhut
Linha de fomento: Auxílio à Pesquisa - Temático