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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #227133
Title: Chronic estrogen deficiency in mice alters FoxO1 signaling in a mixed fiber skeletal muscle

Author
item ROGERS, NICOLE - HNRCA AT TUFTS UNIVERSITY
item PERFIELD, JAMES - HNRCA AT TUFTS UNIVERSITY
item STRISSEL, KATHERINE - HNRCA AT TUFTS UNIVERSITY
item OBIN, MARTIN - HNRCA AT TUFTS UNIVERSITY
item WITCZAK, CAROL - JOSLIN DIABETES CENTER
item GOODYEAR, LAURIE - JOSLIN DIABETES CENTER
item Greenberg, Andrew

Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 5/14/2008
Publication Date: 6/15/2008
Citation: Rogers, N.H., Perfield, J.W., Strissel, K.J., Obin, M.S., Witczak, C.A., Goodyear, L.J., Greenberg, A.S. 2008. Chronic estrogen deficiency in mice alters FoxO1 signaling in a mixed fiber skeletal muscle. Endocrine Society's Annual Meeting. Paper No. 85616.

Interpretive Summary:

Technical Abstract: Menopause, characterized by reduced estrogen levels, is associated with increased adiposity and metabolic pathology. Molecular mechanisms underlying this association between low estrogen status and metabolic disease are not fully elucidated. Dysregulated skeletal muscle fatty acid oxidation (FAO) promotes adiposity, in part due to impairments in PPAR-delta and FoxO1 activity. These transcription factors promote an oxidative muscle phenotype by 1) altering expression of genes involved in glucose metabolism [e.g. pyruvate dehydrogenase kinase (PDK-4)], shifting substrate utilization towards fat, and 2) increasing expression of slow isoforms of contractile proteins such as myosin light chain (MLC) and troponin C, thereby shifting fiber type towards type 1 oxidative. Interestingly, PPAR-delta positively regulates genes associated with atrophy [e.g. atrogin and MuRF] without associated muscle proteolysis. AIM: To investigate ovariectomy-induced alterations in FAO genes in a mixed fiber muscle. METHODS: Mice (10 wk old, C57Bl6/J) were sham operated (n=10) or ovariectomized (OVX, n=11) as a model of menopause, and food intake and body weight were recorded weekly for 10 weeks. At 6-8 weeks post-operation, mice were put in metabolic chambers to assess energy expenditure over 48 h. At 10 weeks, quadriceps muscles were harvested and quantitative real-time PCR used to determine relative gene expression. RESULTS: OVX mice weighed more than sham mice (OVX 27.50 +/- 0.76g, sham 22.76 +/- 0.58g, p<0.001), with 5-fold increases in fat depot weights. OVX mice displayed a 15% decrease in oxygen consumption and heat production, with no significant changes in spontaneous physical activity or food intake. Ovariectomy selectively decreased muscle expression of PPAR-delta and downstream targets PDK-4 and FoxO1. Consistent with these data, FoxO1 targets atrogin and MuRF were downregulated, as were slow isoforms of contractile proteins Troponin C and MLC, suggesting a shift in fiber type. Implications of these changes downstream of FoxO1 are currently under investigation. CONCLUSIONS: Ovariectomy in mice increases adiposity and decreases energy expenditure, with dysregulation of PPAR-delta and FoxO1 pathways eliciting the gene expression profile of a less oxidative muscle.