Vihang Narkar, PhD

Biography

Our laboratory broadly studies transcriptional regulation of metabolic and vascular homeostasis using nuclear receptors as model signaling molecules. Currently, we are investigating the cellular and physiological functions of orphan nuclear receptors (e.g. estrogen-related receptors) and their co-regulators (e.g. PGC1’s). We use a wide-ranging approach including genetically engineered mice, murine disease models, high-throughput gene expression analysis (e.g. RNA-sequencing, ChIP-sequencing), pharmacology, cell signal and in vitro systems in our studies. These tools are being used to investigate the role of ERR’s and PGC1’s in (I) cellular processes such as genome-wide gene orchestration, mitochondrial biogenesis and angiogenesis; (II) physiological phenomenon such as exercise adaptation and whole-body metabolism; as well as (III) diseases such as obesity/diabetes, peripheral arterial disease and muscular dystrophies. Ongoing research in areas collective recognized as ‘Metabolic-Vascular Syndromes’ is described below.

Angiogenesis & Peripheral arterial disease: Nearly 8 million Americans with peripheral arterial disease (PAD) suffer from immobility, ulceration, and impaired wound healing. PAD often occurs in chronic metabolic diseases such as atherosclerosis and diabetes. The pathology of PAD involves significant loss of skeletal muscle vascular supply, which ultimately progresses to critical limb ischemia (CLI) requiring limb amputation. Despite its prevalence, non-invasive interventions for PAD are lacking. Exercise is beneficial; however, it cannot always be prescribed as a treatment because of severe exercise-related muscle pain experienced by PAD patients. We are investigating whether and how nuclear receptor ERR-gamma can stimulate therapeutic angiogenesis in muscle and mitigate PAD. We have found that ERR-gamma activates a paracrine muscle angiogenesis program, and increases transcription and secretion of pro-angiogenic factors (e.g. Vegfa) by muscle, leading to improved vascularization in a pre-clinical model of PAD. ERR-gamma functions independent of hypoxia and hypoxia-inducible factors (HIF), and therefore may have added advantage in diabetes-associated PAD, where HIF signaling is impaired. We are currently examining the role of ERR’s using both gain and loss-of-function models in diabetic vascular complications.

Muscle vascularization depends on a balance between pro and anti-angiogenic factors secreted by the muscle. While regulation of pro-angiogenic factors through nuclear receptors, hypoxia-inducible factors, and kinases is being defined, very little is known on how anti-angiogenic factors are regulated. We have developed pre-clinical murine as well as cellular models to identify that transcriptional co-factor PGC1-beta is a regulator of anti-angiogenic factors in the skeletal muscle, which induces degradation of blood vessels in conditions such as PAD and diabetes. We postulate that PGC1-beta promotes anti-angiogenic gene program by activating nuclear receptor COUP-TFI. In turn, PGC1-beta expression is repressed by hypoxia and HIF, which are both pro-angiogenic triggers. We are currently analyzing the muscle-specific loss-of-function models for PGC1-beta and COUP-TFI in the regulation of angiogenesis in ischemic muscle.

In addition to discovering muscle-expressed regulators that promote paracrine angiogenesis, we are also investigating how nuclear receptors and other transcriptional factors regulate blood vessel growth via signaling in vascular cells.

Exercise Mimetics, Obesity & Diabetic Complications. Exercise is beneficial in preventing obesity, diabetes and cardiovascular complications. Therefore, identifying molecular basis of endurance exercise has emerged as a popular research area due to the potential for synthetically targeting exercise pathways to harness the beneficial effects of exercise. We identified that serine-threonine kinase AMPK and nuclear receptor PPARd agonists exert exercise-like effects in the skeletal muscle to increase high endurance type I myofibers, mitochondrial biogenesis, and overall oxidative capacity leading to increased exercise tolerance. In this work, we also demonstrated that AMPK physically interacts with PPARd to qualitatively and quantitatively influence PPARd endurance gene signature in the skeletal muscle, providing insight into how different pathways may interact to impart exercise adaptations. We are now investigating the potential of already established exercise-mimetic nuclear receptors (e.g. PPAR’s, ERR’s) in preventing metabolic-vascular complications related to obesity and diabetes. We are also identifying novel transcriptional factors and signaling pathways involved in exercise adaptations particularly in the context of metabolic and vascular efficiency.

Muscle degenerative disease and atrophy. Skeletal muscle wasting is common complication of aging, dystrophies, obesity and cardiovascular disease. A part of our research program is focused on understanding whether and how nuclear receptors and its co-regulators control muscle size and regeneration. We recently found that activation of ERR-gamma in skeletal muscle mitigates muscle degeneration and improves function in mdx mice – a model of Duchenne muscular dystrophy (DMD). The unexpected but very important finding of this work was that the ERR-gamma effect was not due to the restoration of the membrane dystrophin-associated glycoprotein complex (DAG). DAG is required for muscle strength, is missing from dystrophic muscles, and is thought to be indispensable in treating dystrophy. Rather, ERR-gamma mitigates muscle dystrophy in part by restoring oxidative metabolism and muscle vascularization, which are both dys-regulated in dystrophic mice. We are further exploring DAG-independent mechanisms of mitigating DMD via nuclear receptor targeting.

In another line of studies, we are making considerable progress in identifying new transcriptional pathways involved in muscle wastage. We have found that sustained activation of PGC1-beta results in progressive loss of skeletal muscle mass, particularly of type II glycolytic myofibers. This muscle loss is due to the activation of a full-scale transcriptional program involving apoptotic and autophagy factors by PGC1-beta. Interestingly, PGC1-beta also increases oxidative metabolism and mitochondrial biogenesis, revealing an unrecognized molecular link between mitochondrial hyper-activation and muscle wasting.

Other research. Through on-going collaborations, we are also making contribution to the areas of molecular metabolism (linking fat droplet protein perilipin 5 to PGC1-alpha mediated transcription), calcium signaling (linking between calcium homeostasis and ERR-gamma signaling) and exercise physiology (regarding co-targeting of myostatin and ERR-gamma to test the engineering constraints of generating mice with hypertrophic muscle with high aerobic capacity).