Hypoxia induces differential acute and chronic adaptations in regulation of skeletal muscle protein turnover

Hypoxia may be a trigger of skeletal muscle atrophy in acute and chronic respiratory disease. To test this hypothesis, short- and long-term regulation of muscle mass in response to normobaric hypoxia was investigated in mice. During 48h, O 2 – levels were reduced stepwise to 8%, which was maintained for 21 days. Food intake was monitored daily and mice were sacrificed at days 4 and 21. mRNA and protein expression levels were determined in gastrocnemius muscle. Food intake was affected during short- (day (d) 4: -50%) and long-term (d21: -20%) hypoxia. Compared to normoxia, gastrocnemius muscle weight decreased (d4: -7.5% and d21: -11.9%). The reduced food intake was partially responsible for this effect. Hypoxia increased expression of Atf4 (d4: +52%, d21: +31%) and Gadd34 (d4: +148%, d21: +73%) indicative for acute and chronic ER stress signaling. Protein synthesis regulation was differentially affected by short- and long-term hypoxia (p-eIF2α d4: -29% and d21: -23%, p-4EBP1 d4: not significant (ns) and d21: +36%). Atrogin-1 as proteasomal protein degradation marker was activated during acute and chronic hypoxia (d4: +128%, d21: +60%), whereas MuRF1 only at day 4 (d4: +102%, d21: ns) and was explained by reduced food intake. short- and long-term hypoxia induced markers of lysosomal protein degradation Bnip3 (d4: +95%, d21: +74%) and Lc3 (d4: +18%, d21: +26%) which could be attributed in part to the reduced food intake. In conclusion, these data suggest that acute adaptation of muscle mass to hypoxia reflects an increased protein degradation, whereas chronic adaptation may involve increased protein turnover. Supported by the Dutch Top Institute Pharma (project # T1-201).