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Principal Investigator: Rebecca L Scalzo
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Type 2 Diabetes (T2D) is a major health priority within the VA. More than 24% of Veterans have T2D, twice
the national average. There is an increasing population of female veterans in the VA in the premenopausal age
range. Premenopausal women with T2D have poorer health-related outcomes compared with age-matched
men with T2D. The mechanisms for this sex difference in T2D are unknown. Aerobic power predicts the
incidence of the poor health-related outcomes associated with T2D. T2D negatively impacts aerobic power to a
greater degree in premenopausal women with T2D compared with men with T2D. Aerobic power is partially
dependent on skeletal muscle bioenergetics. This proposal is designed to address a clinically significant
knowledge gap related to women with T2D, to identify potential targets for clinical therapies to improve the
health of women with T2D, and to provide training in several specific methods that will prepare me for a
successful transition to independence.
Aerobic power is partially dependent on skeletal muscle bioenergetics: signaling associated with and measures
of cellular energy balance and mitochondrial biogenesis/function. Estrogen (E2) signaling is reported to be
supportive of skeletal muscle bioenergetics, however, my surprising preclinical data suggest that the
physiological context in which estrogen signaling is studied is important. My pilot data reveal an unexpected
adverse interaction of E2 and diabetes on the regulators of skeletal muscle bioenergetics. My working
hypothesis is that diabetes suppresses E2-mediated support of bioenergetics in skeletal muscle of
reproductive aged female rats. I will address this hypothesis with two specific aims:
Aim 1: To test the impact of the diabetic environment on skeletal muscle E2 signaling and mitochondrial
biogenesis in vitro. This aim will determine impact of diabetes on E2-mediated support of signaling associated
with and measures of cellular energy balance and mitochondrial biogenesis. Through intricate signaling studies
data will be generated to identify the diabetes-associated mechanism(s) that could be targeted to restore
mitochondrial bioenergetics in women with T2D.
Aim 2: To understand whether the disruption of E2 support of skeletal muscle bioenergetics in vivo by diabetes
impairs exercise capacity. This aim will determine the bioenergetic consequences of the diabetes-associated
disruption of E2 support of skeletal muscle through measures of substrate utilization, mitochondrial function,
and aerobic exercise capacity.
This proposal addresses the clinically relevant knowledge gap related to decreased functional status of
premenopausal women with T2D and could identify potential targets for clinical therapies to improve the health
of women with T2D. Through training with my mentors, coursework, and the successful completion of the
project specific aims, I will further develop my knowledge base and skillset in primary cell culture, cellular
signal transduction, and manipulation of E2 and derive new data that will set me on the path to achieve my
overall goal of becoming a successful, independent VA scientist.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><1-Phosphatidylinositol 3-Kinase><3'5'-cyclic ester of AMP><3-Phosphoinositide Dependent Protein Kinase-1><5'-AMP-activated protein kinase><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><Address><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult-Onset Diabetes Mellitus><Aerobic><Aerobic Activity><Aerobic Exercise><Aerobic Training><Aerobic fitness><Affect><Age><Animal Model><Animal Models and Related Studies><Aquadiol><Attenuated><Bioenergetics><Biogenesis><Biological><Cardiovascular Diseases><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Clinical><Common Rat Strains><Culturing, in vitro Vertebrate, Primary><Cyclic AMP><Data><Diabetes Mellitus><Diet><Differences between sexes><Differs between sexes><Dimenformon><Diogyn><Diogynets><Disparities><Disparity><ENOS><Endothelial Nitric Oxide Synthase><Environment><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogens><Exercise><Exposure to><Fat-Restricted Diet><Female><Female Health><Goals><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Health><Health Priorities><High Fat Diet><Impairment><In Vitro><Incidence><Intracellular Communication and Signaling><Investigators><Ketosis-Resistant Diabetes Mellitus><Knowledge><Low-Fat Diet><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Mentors><Methods><Mice><Mice Mammals><Mitochondria><Molecular Target><Murine><Mus><Muscle><Muscle Fibers><Muscle Tissue><Myotubes><NIDDM><NOS3><NOS3 gene><Nitric Oxide Synthase 3><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Oophorectomy><Origin of Life><Outcome><Ovariectomy><Ovocyclin><Ovocylin><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PKB Kinase><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><Pathway interactions><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiologic><Physiological><Population><Pre-Menopause><Pre-menopausal Period><Premenopausal><Premenopausal Period><Premenopause><Prevalence><Primary Cell Cultures><Process><Progynon><PtdIns 3-Kinase><Rat><Rats Mammals><Rattus><Reporting><Research Personnel><Researchers><Respiration><Rhabdomyocyte><Role><Scientist><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><System><T2 DM><T2D><T2DM><Testing><Therapeutic Estradiol><Therapeutic Estrogen><Thiazolidinedione Receptor><Training><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Phosphatidylinositol Kinase><Type II Diabetes Mellitus><Type II diabetes><Type III Phosphoinositide 3-Kinase><Type III nitric oxide synthase><VO2 max><VO2max><Veterans><Voluntary Muscle><Wistar Rats><Woman><Women's Health><adenosine 3'5' monophosphate><adult onset diabetes><aged><ages><antagonism><antagonist><attenuate><attenuates><biologic><biological signal transduction><cAMP><cardiovascular disorder><cell culture><cell cultures><clinical relevance><clinical significance><clinically relevant><clinically significant><design><designing><diabetes><diabetic><diets><energy balance><estrogen disrupting><estrogen disruption><estrogenic disruption><exercise capacity><experiment><experimental research><experimental study><experiments><female gonadectomy><functional status><hPDK1><hydroxymethylglutaryl-CoA-reductase kinase><improved><in vivo><inhibitor><insight><ketosis resistant diabetes><knowledge base><maturity onset diabetes><maximal oxygen uptake><men><military veteran><mitochondrial><model of animal><mortality><muscular><pathway><pre-clinical><pre-menopausal><preclinical><premenopausal status><programs><protein kinase B kinase><reproductive><respiratory mechanism><response><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><skills><social role><sugar><training opportunity><type 2 DM><type II DM><type two diabetes><veteran population>