Deb Muoio, PhD

Director of Basic Research, Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center

Position

Professor Departments of Medicine (Division of Endocrinology, Metabolism, and Nutrition) Duke University Medical Center

Contact

Carmichael Building

919 479 2328

debbie.muoio@duke.edu

Summary

Deb Muoio is a Professor in Medicine, Division of Endocrinology, and Director of Basic Research at the Duke Molecular Physiology Institute. She earned a PhD in Nutritional Biochemistry at the University of North Carolina, Chapel Hill, followed by postdoctoral fellowships at East Carolina and Duke Universities working in the areas of muscle physiology and metabolic disease. Her laboratory studies mechanisms of metabolic control and molecular events that link nutrition and exercise to health outcomes. Her research program features a translational approach that combines basic science and human studies with mass spectrometry-based metabolomics to identify metabolite signatures of mitochondrial dysfunction and cardiometabolic disease. The overarching goal of this work is to guide the development of new lifestyle, nutraceutical and/or pharmacological strategies to maintain mitochondrial and metabolic health. 

PhD, University of North Carolina, Chapel Hill, NC

The overarching goal of the laboratory is to identify metabolic mechanisms that link lifestyle factors such as overnutrition and physical inactivity to poor health outcomes.  Projects are thematically focused on the interplay between diet, exercise and skeletal muscle mitochondrial function, and are co-led by our DMPI faculty colleague, Dr. Tim Koves.  In addition to their critical roles in ATP production and cellular bioenergetics, mitochondria are increasingly recognized as a key regulatory hub for processes such as nutrient sensing, retrograde signaling, autophagy, growth and cell survival.  Aberrant mitochondrial performance is evident in a broad range of disease states, including diabetes, cardiovascular disease, cancer and numerous age-related disorders.   Our work aims to define and understand the biological networks that maintain mitochondrial integrity and energy homeostasis.  Main project areas include: 1) mechanisms that link nutrient oversupply and intramuscular lipid accumulation to mitochondrial stress and insulin resistance, 2) mechanisms through which habitual exercise enhances mitochondrial function, energy homeostasis and insulin sensitivity, and 3) translational studies that examine the impact of diet and/or exercise interventions on metabolic regulation and mitochondrial function in human skeletal muscle.

Our program features a multidisciplinary approach that combines integrative physiology and systems biology with cell and molecular biology, using model systems ranging from isolated mitochondria to primary human myocytes and genetically engineered mice.  Many of the projects apply mass spectrometry-based metabolomics as a tool to pinpoint sites of regulation and dysregulation in the context of contrasting physiological and pathophysiological paradigms.  This approach led us to identify a cluster of acylcarnitine metabolites that derive from mitochondrial acyl-CoA intermediates and track with nutrient- (1,4) and exercise- (2,3) induced changes in mitochondrial function and insulin action.  This signature emerged from studies in rodents (4,5,6,7,9) and humans (8,9,10,11).  The conversion of acyl-CoA molecules to their respective acylcarnitine conjugates permits mitochondrial export of excess carbon.  Mounting evidence suggests these metabolites are produced by nutrient overloaded mitochondria as an attempt at stress relief (12).  In support of this model we found that dietary L-carnitine supplementation administered to obese rodents increased tissue production and efflux of acylcarnitines while also improving mitochondrial performance and whole body glucose homeostasis (5,6,7).  The mechanistic basis of these observations is under investigation in studies that employ genetic engineering strategies to manipulate acylcarnitine production in rodent and cell culture models (4,6,9,14).

One of the core projects in the lab that evolved from the foregoing work centers on delineating the physiological relevance of acylcarnitine efflux. The most abundant acylcarnitine species, acetylcarnitine, is synthesized by carnitine acetyltransferase (CrAT), a member of the carnitine acyltransferase family that localizes to the mitochondrial matrix.  CrAT strongly prefers acetyl-CoA and other short chain acyl-CoA end products of fatty acid, glucose and amino acid catabolism.   We recently found that obesity and lipid stress lower CrAT activity in muscle and heart (13).  Moreover, CrAT deficiency in mice disrupts glucose control (9), mitochondrial fuel selection (9) and exercise tolerance (15); and ongoing studies point to a critical role for CrAT in mitigating nutrient-induced lysine acetylation of mitochondrial proteins (16).  In sum, this work positions acylcarnitine efflux as a critical process to relieve mitochondrial carbon load, and suggests that elevated serum acylcarnitines serve as a novel biomarker of organelle stress.  These discoveries are expected to guide the development of new lifestyle, nutraceutical and/or pharmacological strategies to treat and prevent cardiometabolic disorders.  Projects were and/or are supported by grants from NIDDK, NHLBI, NIA and the American Diabetes Association. 

15. Sarah Seiler, Timothy Koves, Jessica Gooding, Kari Wong, Bob Stevens, Olga Ilkayeva Karen DeBalsi and Deborah Muoio.  Carnitine Acetyltransferase Offsets Energy Stress and Delays Muscle Fatigue During Strenuous Exercise. Submitted

16. Michael Davies, Lilja Kjalarsdottir, Laura Dubois, Dorothy Slentz, Olga Ilkayeva, Will Thompson and Deborah Muoio. Carnitine Acetyltransferase Defends Against Hyperacetylation of Mitochondrial Proteins.  Abstract presented at Cold Spring Harbor Symposium on Metabolic Signaling and Disease.  Cold Spring Harbor, New York, 2013.

Faculty

Tim Koves, PhD, MBA

Guofang Zhang, PhD

Staff

Scott Crown

James Draper

Paul Grimsrud, PhD

Tara Narowski

Alexander Padgett

Dorothy Slentz

Postdocs / Fellows

Kelsey Fisher-Wellman, PhD

Ashley Williams, PhD

Graduate/Medical Students

Mike Davidson