Sustained exposure to glucocorticoids promotes muscle remodeling and shifts metabolic phenotype in elephant seal myotubes

Abstract

Elephant seals exhibit extreme behaviors characterized by sustained glucocorticoid (GC) elevations without deleterious consequences for their fitness and no signals of muscle atrophy, but the cellular mechanisms that allow them to survive such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, imaging, and functional analyses to explore the underpinnings of GCs tolerance in elephant seals. Elephant seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to the GC dexamethasone at three ascending doses (0.1, 1, and 100mM) for 48h resulted in changes in gene expression of 6 clusters of genes related to the structural constituents of muscle and pathways associated with energy metabolism and cell survival including PI3K signaling. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses of catabolic and muscle structural genes corroborated that the observed effects are mediated by GR. Sustained exposure to GCs also reduced oxygen consumption rates (OCR), shifted the metabolic phenotype towards glycolysis, and induced mitochondrial fission and dissociation of mitochondria-ER interactions, without reducing the cell viability. Knockdown of ddit4, a GR-regulated gene involved in mitochondria-ER dissociation, recovered OCR and upregulated genes involved in redox balance. Overall, these results show that adaptation to sustained glucocorticoid exposure in elephant seal muscle cells involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased mitochondrial metabolism and cell survival.