Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/20/2009
Publication Date: 1/20/2010
Citation: Rogers, N.H., Perfield, J.W., Strissel, K.J., Obin, M.S., Greenberg, A.A. 2010. Ovarian function in mice results in abrogated skeletal muscle PPARdelta and FoxO1-mediated gene expression. Biochemical and Biophysical Research Communications. 392:1-3. Interpretive Summary: Estrogen increases the characteristics of skeletal muscle that can burn fat. When women stop producing estrogen during the transition to menopause they are at increased risk of developing obesity. However, the protective anti-obesity actions of estrogen are poorly understood. ARS-funded researches from Tufts University in Boston, MA compared the characteristics of skeletal muscle in female mice that have lost the ability to produce estrogen as compared to female mice which produce estrogen normally. Our studies demonstrated that estrogen acts on muscle to produce a group of proteins that enhances the ability of muscle to burn fat. The results of this study demonstrate an important mechanism by which estrogen functions in women to protect against the development of obesity. Importantly this observation will direct researchers to investigate and identify nutrients that will mimic estrogen’s actions on skeletal muscle to facilitate fat burning.
Technical Abstract: Menopause, the age-related loss of ovarian hormone production, promotes increased adiposity and associated metabolic pathology, but molecular mechanisms remain unclear. We previously reported that estrogen increases skeletal muscle PPARDelta expression in vivo, and transgenic mice overexpressing muscle-specific PPARDelta are reportedly protected from diet-induced obesity. We thus hypothesized that obesity observed in ovariectomized mice, a model of menopause, may result in part from abrogated expression of muscle PPARDelta and/or downstream mediators such as FoxO1. To test this hypothesis, we ovariectomized (OVX) or sham-ovariectomized (SHM) 10-week old female C57Bl/6J mice, and subsequently harvested quadriceps muscles 12 weeks later for gene expression studies. Compared to SHM, muscle from OVX mice displayed significantly decreased expression of PPARDelta (3.4-fold), FoxO1 (4.5-fold), PDK-4 (2.3-fold), and UCP-2 (1.8-fold). Consistent with studies indicating PPARDelta and FoxO1 regulate muscle fiber type, we observed dramatic OVX-specific decreases in slow isoforms of the contractile proteins myosin light chain (11.1-fold) and troponin C (11.8-fold). In addition, muscles from OVX mice expressed 57% less myogenin (drives type I fiber formation), 2-fold more MyoD (drives type II fiber formation), and 1.6-fold less musclin (produced exclusively by type II fibers) than SHM, collectively suggesting a shift towards less type I oxidative fibers. Finally, and consistent with changes in PPARd and FoxO1 activity, we observed decreased expression of atrogin-1 (2.3-fold) and MuRF-1 (1.9-fold) in OVX mice. In conclusion, muscles from ovariectomized mice display decreased PPARDelta and FoxO1 expression, abrogated expression of downstream targets involved in lipid and protein metabolism, and gene expression profiles indicating less type I oxidative fibers.