Differential adaptation of glycolytic and oxidative muscles to hypoxia

Abstract

BackgroundCOPD‐associated skeletal muscle atrophy is found in glycolytic rather than oxidative muscle fibers. We hypothesize that hypoxia is a trigger for this fiber type‐specific atrophy.MethodsMice were kept under normoxia or hypoxia. Oxygen levels were reduced stepwise to 8% during 48h, and maintained for 21 days. Food intake was monitored and mice were sacrificed at days 4 and 21.ResultsReduction of oxidative (Soleus) muscle weight was due to hypoxia‐induced hypophagia. Glycolytic (EDL) muscle weight reduction involved additional hypophagia‐independent effects. Cross sectional area (CSA) of individual fibers was reduced in glycolytic but not oxidative muscle. Expression of genes involved in proteasomal and lysosomal protein degradation, ER stress and glucocorticoid receptor (GR) signaling were increased in both muscles. In glycolytic muscle, upregulation could not be explained by hypophagia alone. Capillary contacts per fiber CSA increased in both muscles. In oxidative muscle, this was due to a reduction of the interstitial space, whereas in glycolytic muscle fiber CSA decreased.ConclusionsMuscle mass, muscle fiber CSA, proteolysis, ER‐stress and GR signaling are more affected by hypoxia in glycolytic than oxidative muscle. In oxidative, but not glycolytic muscle, these alterations are accounted for by hypophagia.Supported by the Dutch Top Institute Pharma (project # T1‐201).