Yaxin Zhao, Marta Vuckovic, Hong Sik Yoo, Nina Fox, Adrienne Rodriguez, Kyler McKessy, and Joseph L. Napoli∗
Graduate Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, The University of California-Berkeley, Berkeley, California, USA
Joseph L. Napoli: [email protected]
Cell Biology, Medical Research
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.
Stained slides were examined at 40× magnification with oil immersion using Zeiss Axiovert M1 fluorescent microscope equipped with Hamamatsu Orca CCD camera and CoolLED pE-300 white LED illuminator, and Zeiss Z1 AxioObserver inverted microscope equipped with a 40× immersion lens, X-Cite 120 LED fluorescence source and Qimaging Retiga SRV CCD camera (Biological Imaging Facility, UC Berkeley).
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The pE-300white is a popular illuminator for everyday fluorescent screening and analysis with simple operatation and individual irradiance control of each LED channel.
The Journal of Biological Chemistry
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