ERα Governs the Sexual Dimorphism in HSP72-mediated Control of Mitochondrial Function, Exercise Capacity, and Insulin Sensitivity in Mice

Authors

Noelle Morrow, University of California, Los AngelesFollow
Amanda Lin, University of California, Los Angeles
Zhenqi Zhou, University of California, Los Angeles
Hirotaka Iwasaki, University of California, Los Angeles
Brian Drew, Monash University
Mark Febbraio, Monash University
Andrea Hevener, University of California, Los AngelesFollow

Abstract

HSP72 is a chaperone protein upregulated during exercise. Levels are reduced in aging and obesity, and increased levels are correlated with improvements in metabolic health in male mice and humans. Male HSP72KO mice have increased body fat, decreased insulin sensitivity, and a loss of mitochondrial quality control. Specifically, male KO mice have increased cytosolic Parkin levels, but the protein is unable to move to the mitochondria resulting in enlarged, hyperfused mitochondria associated with metabolic dysfunction. PURPOSE: To investigate the role of HSP72 in female mice to better understand the sexual dimorphism involved in the heat shock response. METHODS: HSP72KO and WT male and female mice were analzyed for insulin sensitivity, expercise capacity, gene and protein expression, and mitochondrial morphology and respiratory capacity. RESULTS: Overall, female HSP72KO mice showed the opposite of male KO mice. Female KOs had reduced body weight (p<0.0001) and gonadal fat (p=0.005), improved insulin sensitivity (p=0.0179), and increased voluntary wheel running compared to WT controls and male mice (p=0.0079). Cytosolic Parkin was increased, but maintained its ability to translocate to the mitochondria. Hence, skeletal muscle mitochondria were smaller and more spherical in the KO mice, indicative of increased fission signaling. Respirometry analysis showed enhanced complex I, II, and IV activity in the mitochondria of skeletal muscle (p=0.0127, 0.003, & 0.0009). The improved insulin sensitivity, exercise capacity, and mitochondrial fission in female KO mice mimics the phenotype of estrogen receptor a (ERa) overexpression mice, and female HSP72 KO mice showed increased levels of ERa and its encoding gene, while the male KO mice did not. CONCLUSION: Given the fact that KO males are negatively affected by the loss of HSP72 and do not show an increase in ERa, this sexual dimorphism appears underpinned by a compensatory upregulation of the estrogen receptor alpha (ERa). The beneficial, and potentially therapeutic, role of HSP72, as well as the consequences associated with reduced levels of the protein, has been repeatedly demonstrated in male mice and humans. These data indicate that HSP72 plays a unique role in the regulation of metabolic and mitochondrial health in females.

Recommended Citation

Morrow, Noelle; Lin, Amanda; Zhou, Zhenqi; Iwasaki, Hirotaka; Drew, Brian; Febbraio, Mark; and Hevener, Andrea (2024) "ERα Governs the Sexual Dimorphism in HSP72-mediated Control of Mitochondrial Function, Exercise Capacity, and Insulin Sensitivity in Mice," International Journal of Exercise Science: Conference Proceedings: Vol. 14: Iss. 4, Article 6.
Available at: https://digitalcommons.wku.edu/ijesab/vol14/iss4/6