title: Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism.
abstract: 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% O2for 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 & NOTEWORTHYSince 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.
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Franciele
authors.initials: F
authors.lastname: Przygodda
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.|Federal University of Fronteira Sul, Chapecó, Santa Catarina, Brazil.
authors.forename: Leandro Henrique
authors.initials: LH
authors.lastname: Manfredi
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Juliano
authors.initials: J
authors.lastname: Machado
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.|Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; and.
authors.forename: Dawit A P
authors.initials: DAP
authors.lastname: Gonçalves
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Neusa M
authors.initials: NM
authors.lastname: Zanon
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Leni G H
authors.initials: LGH
authors.lastname: Bonagamba
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Benedito H
authors.initials: BH
authors.lastname: Machado
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.|Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; and.
authors.forename: Ísis C
authors.initials: ÍC
authors.lastname: Kettelhut
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; navegantes@fmrp.usp.br.
authors.forename: Luiz C C
authors.initials: LCC
authors.lastname: Navegantes
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D009124:Muscle Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D002118:Calcium
keywords: adrenalectomy; hypoxia; insulin resistance; muscle atrophy; protein metabolism