PROJECT SUMMARY
Diabetes is a leading cause of peripheral arterial disease (PAD), a cardiovascular complication characterized by
blood vessel regression, ischemia, mitochondrial dysfunction and limb myopathy. Classic angiogenic regulators
such as Vegfa, which have been a major focus of therapeutic interventions have proved to be inefficient clinically.
Consequently, pharmacological treatment of PAD has remained an unmet medical need, leading to limb
amputations in nearly 200,000 patients every year. Rehabilitative exercise has emerged as an effective clinical
strategy for managing PAD by virtue of its stimulatory effects on oxidative metabolism and vascularization in the
limb musculature. However, a common limitation of physical therapy is that majority of PAD patients, especially
ones with diabetes, cannot exercise due to severe leg pain or other cardiovascular complications. Therefore,
characterizing molecular regulation of metabolic and vascular remodeling in exercise and diabetes may present
novel targets for treating PAD. In this study, we will investigate the role of nuclear receptor estrogen-related
receptor alpha (ERR¿) in regulating metabolic capacity, vascular supply and exercise capacity in murine models
of exercise, diabetes and ischemia. We will also investigate mechanisms regulating ERR¿ expression and
activity in the skeletal muscles. We hypothesize that (I) ERR¿ is responsible for exercise-mediated metabolic
and vascular remodeling in the skeletal muscle, (II) overexpression of ERR¿ in the skeletal muscles of diabetic
mice mitigates diabetic PAD-like pathology in absence of exercise, and (III) HIFs regulate ERR¿ expression and
signaling in the skeletal muscle. The hypothesis will be tested in three aims. In Aim 1, we will investigate the role
of ERR¿ in regulating metabolic and vascular characteristics of the limb musculature at baseline and in response
to exercise. In Aim 2, we will investigate whether ERR¿ activation can mitigate PAD-like pathology in diabetic
mice. In Aim 3, we will investigate the function of hypoxia-inducible factors (HIFs) in the regulation of ERR¿
expression and activity in the skeletal muscle. For these studies, we will use muscle-specific targeting of ERR¿
in transgenic mice, as well as intramuscular AAV9-ERR¿ delivery to examine effect on exercise, diabetes and
ischemic adaptations. In addition, we will use cellular mechanistic approach to further elucidate metabolic and
paracrine angiogenic regulation by muscle ERR¿, as well as regulation of ERR¿ by HIFs. We expect our work
to demonstrate that ERR¿ is a central regulator of muscle metabolic and vascular capacity in exercise, diabetes
and ischemia, and highlight ERR¿ as a potential therapeutic candidate for treating diabetes-associated PAD.