Retinoic acid exerts sexually dimorphic effects on muscle energy metabolism and function

Abstract

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces adiposity. Skeletal muscle contributes to preventing adiposity, by consuming nearly half the energy of a typical human. We report sexually dimorphic differences in energy metabolism and muscle function in Rdh10 +/− mice. Relative to wild-type (WT) controls, Rdh10 +/− males fed a high-fat diet decrease reliance on fatty-acid oxidation and experience glucose intolerance and insulin resistance. Running endurance decreases 40%. Rdh10 +/− females fed this diet increase fatty acid oxidation and experience neither glucose intolerance nor insulin resistance. Running endurance increases 220%. We therefore assessed RA function in the mixed-fiber type gastrocnemius muscles (GM), which contribute to running, rather than standing, and are similar to human GM. RA levels in Rdh10 +/− male GM decrease 38% relative to WT. Rdh10 +/− male GM increase expression of Myog and reduce Eif6 mRNAs, which reduce and enhance running endurance, respectively. Cox5A, complex IV activity, and ATP decrease. Increased centralized nuclei reveal existence of muscle malady and/or repair in GM fibers. Comparatively, RA in Rdh10 +/− female GM decreases by less than half the male decrease, from a more modest decrease in Rdh10 and an increase in the estrogen-induced retinol dehydrogenase Dhrs9 . Myog mRNA decreases. Cox5A, complex IV activity, and ATP increase. Centralized GM nuclei do not increase. We conclude that Rdh10/RA affects whole body energy use and insulin resistance partially through sexual dimorphic effects on skeletal muscle gene expression, structure, and mitochondria activity.

The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription

“…Ablation of the retinol dehydrogenase Rdh1 leads to adiposity in mice fed a low-fat diet by disrupting brown adipose tissue adaptation to refeeding ( Krois et al., 2019 ). Heterozygote ablation of the retinol dehydrogenase Rdh10 increases adiposity in mice fed a high-fat diet ( Yang et al., 2018 ; Zhao et al., 2021 ). Rdh10 +/− males develop glucose intolerance and insulin resistance and have dysfunctional mitochondria in muscle.…”

Retinoid metabolism: new insights

“…Additionally, in males, running endurance decreases, while for females, running endurance increases. These sexually dimorphic effects are in part the result of different amounts of reduction in RA levels in these RDH10+/− male vs female mice, since low-dose RA, given chronically, can correct these metabolic pathologies (Yang et al 2018, Zhao et al 2021.…”

Retinoic Acid: Sexually Dimorphic, Anti-Insulin and Concentration-Dependent Effects on Energy

“…Each depends on the presence of the entire metabolon for substrates and often for expression intensity. For example, Dhrs9 represses Aldh1a1 mRNA; the loss of Rdh1 results in decreases in Cyp26b1 and increases in Dhrs9 and Aldh1a1 mRNA; partial ablation of Rdh10 associates with increased Dhrs9 expression in female muscles [13,21,22].…”

“…The homozygous Rdh10 knockout mouse dies at no later than E12.5 with multiple defects, including aspermatogenesis, dysfunctional pancreas development, and neurological and limb malformations [57,[121][122][123][124][125]. On the other hand, the heterozygote (R10Het) lives and reproduces, permitting postnatal assessment of endogenous RA function [22,24]. RA concentrations decreased ≤ 25% in R10Het male and female livers and white fat depots.…”