Menopause begins in the fifth decade of life and results in decreased circulating estrogens which coincides with increases in visceral fat mass placing women at elevated risk for the developing the metabolic syndrome. With the release of the Women's Health Initiative doctors have to reconsider current options for treating postmenopausal women. It is increasingly important to understand the physiological consequences of the loss of ovarian hormones (i.e. estrogens) on women's health so new interventions can be developed. Our data indicate that ovariectomized animals (OVX) exhibit symptoms of the metabolic syndrome, including increased visceral fat, impaired glucose dynamics and high circulating levels of lipid. We believe these changes in the OVX mice are due to a reduced ability of the skeletal muscle to effectively oxidize lipid, which we hypothesize is mediated in part by the gene breast cancer early onset 1 (BRCA1). This study will delineate the role of BRCA1 in regulating lipid entry into the mitochondria of skeletal muscle and attempt to determine if decreases in BRCA1 expression contribute to increased abdominal obesity in the OVX model.

Public Health Relevance

Large decreases in circulating estrogen concentration either via menopause or surgical ovariectomy results in increased visceral adiposity. Since estrogen therapy is not considered a viable option, this proposal will seek to understand how skeletal muscle changes when exposed low levels of estrogens over an extended period of time. Here, we have designed an in-depth exploratory study that will address the dysregulation of cellular mechanisms that regulate lipid utilization in post-menopausal women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR059913-02
Application #
8286172
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2011-06-20
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$159,655
Indirect Cost
$43,284
Name
University of Maryland College Park
Department
Miscellaneous
Type
Schools of Public Health
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Schuh, Rosemary A; Jackson, Kathryn C; Schlappal, Anna E et al. (2014) Mitochondrial oxygen consumption deficits in skeletal muscle isolated from an Alzheimer's disease-relevant murine model. BMC Neurosci 15:24
Jackson, Kathryn C; Gidlund, Eva-Karin; Norrbom, Jessica et al. (2014) BRCA1 is a novel regulator of metabolic function in skeletal muscle. J Lipid Res 55:668-80
Jackson, Kathryn C; Wohlers, Lindsay M; Lovering, Richard M et al. (2013) Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice. Am J Physiol Regul Integr Comp Physiol 304:R206-17
Spangenburg, Espen E; Jackson, Kathryn C; Schuh, Rosemary A (2013) AICAR inhibits oxygen consumption by intact skeletal muscle cells in culture. J Physiol Biochem 69:909-17
Schuh, Rosemary A; Jackson, Kathryn C; Khairallah, Ramzi J et al. (2012) Measuring mitochondrial respiration in intact single muscle fibers. Am J Physiol Regul Integr Comp Physiol 302:R712-9