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bioRxiv · 10.1101/2021.02.05.429992

Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype

Torres-Velarde, J. M.·Kolora, S. R. R.·Khudyakov, J. I.·Crocker, D. E.·Sudmant, P. H.·Vazquez-Medina, J. P.
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Abstract

Elephant seals experience natural periods of prolonged food deprivation while breeding, molting, and undergoing postnatal development. Prolonged food deprivation in elephant seals increases circulating glucocorticoids without inducing muscle atrophy, but the cellular mechanisms that allow elephant seals to cope with such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, and morphological analyses to study how seal cells adapt to sustained glucocorticoid exposure. Seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to dexamethasone at three ascending concentrations for 48h modulated the expression of 6 clusters of genes related to structural constituents of muscle and pathways associated with energy metabolism and cell survival. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses corroborated that GR mediates the observed effects. Dexamethasone also decreased cellular respiration, shifted the metabolic phenotype towards glycolysis, and induced mitochondrial fission and dissociation of mitochondria-ER interactions without decreasing cell viability. Knockdown of DDIT4, a GR target involved in the dissociation of mitochondria-ER membranes, recovered respiration and modulated antioxidant gene expression. These results show that adaptation to sustained glucocorticoid exposure in elephant seal myotubes involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased respiration without compromising cell survival.

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Torres-Velarde, J. M., Kolora, S. R. R., Khudyakov, J. I., Crocker, D. E., Sudmant, P. H., Vazquez-Medina, J. P.. 2021-02-07. Elephant seal muscle cells adapt to sustained glucocorticoid exposure by shifting their metabolic phenotype. https://doi.org/10.1101/2021.02.05.429992

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