Myostatin deletion alters hormone metabolism shifts in obese skeletal muscle of C57/Bl6 mice
Authors: Rosewater Cody , Speese Drew , Padgett Caleb , Mintz James , Brown Zach , Fulton David , Stepp David 
Published: May 2024

Objective: Myostatin deletion improves cardiometabolic disease outcomes observed in obesity without any changes in activity in mice. Hormone balance is dysregulated in obesity, resulting in low testosterone and high estradiol levels, which have been shown to correlate with higher risk for developing associated cardiometabolic disease outcomes. However, the basis of these alterations and how they impact factors that improve obese cardiometabolic outcomes are unknown. Methods: Control and obese mice ( db/db) with or without myostatin deletion to induce hypermuscularity were used. Plasme from mice were analyzed for hormone levels via radioimmunoassay (RIA). Aromatase inhibition was performed via dosing 10mg/kg/day via water. Quantitative PCR was used cytochrome P450 enzymes involved in estrogen metabolism in the liver, skeletal muscle, and visceral white adipose tissue. C2C12 overexpression of CYP1B1 and treatment with hydroxyestrogens in vitro was performed and respective enzyme mRNA expression assessed. Results: Deletion of myostatin increased muscle mass by >30% and resulted in and improved glucose tolerance in the context of obesity without any changes in activity. Obesity decreased plasma testosterone 30% and increased estrogen 20% with no change in gonadal weight, which was improved in the absence of myostatin. CYP1B1, an enzyme that converts estradiol to toxic hydroxy estrogens, showed 2.5-fold expression in obese skeletal muscle, which is reduced in the absence of myostatin, with no change in other cytochrome P450s involved in estrogen metabolism. Inhibition of aromatase reduces estrogen and improves testosterone plasma concentration, indicating the excess estrogen in obesity is derived primarily from testosterone conversion. Aromatase expression was increased in obesity but unaffected by changes in muscle mass, this indicates an alteration to downstream estrogen metabolism. In C2C12 cells, overexpression of myostatin recapitulated changes in CYP1B1 expression seen in vivo, suggesting a direct link between the myokine and sex hormone metabolism. In addition, treatment of C2C12 cells with CYP1B1 derived hydroxyestrogens caused a tandem increase in SCD1 expression, indicating a causal link between CYP1B1 activity in obesity to increased triglyceride synthesis. Conclusion: In summary, obesity causes a shift in sex hormone levels towards estrogen production, which is improved by myostatin deletion. A potential mechanism responsible could be altered estrogen metabolism, leading to decreased estrogen levels without restoration of androgen levels. These data suggest CYP1B1 drives the conversion of estrogen to hydroxestrogens, known to harbor carcinogenic and pro-lipidemic influences, in skeletal muscle which may also contribute to cardiometabolic disease. Whether targeting CYP1B1 improves cardiometabolic function in obesity remains to be determined.

D.W. Stepp and D.J. Fulton are supported by NIH 1R01HL147159.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.