The focus of the Cortright laboratory is to better understand cellular bioenergetics and metabolism, with emphasis on skeletal muscle, in order to develop strategies to treat obesity and type II diabetes. In this regard, studies examining the effects of exercise on mitochondrial bioenergetics and substrate utilization are employed. Technologies examining mitochondrial respiration, genomics and proteomics are used. Models involving cell culture of human myotubes, in vitro assessments of human and rodent skeletal muscle biopsies, and free living animals and humans are utilized in experimental designs.
Principle Investigator – Cortright, R.N. East Carolina Diabetes Obesity Research Institute. Impaired Mitochondrial Function in Skeletal Muscle of African-American vs. Caucasian Women.
Obesity and diabetes is also more than twice as prevalent among African-American women (AAW) than among Caucasian women (CW) in the United States (CDC Report 2011,9). Based on recent findings from our lab (8,14), we hypothesize that skeletal muscle mitochondrial function is altered in AAW vs. CW leading to reduced respiratory capacity, elevated free radical production/oxidative stress, and a greater propensity to develop obesity, insulin resistance, and diabetes. Using state-of-the-art permeabilized muscle fiber techniques, the proposed studies will address this hypothesis by focusing on two aspects of mitochondrial function: 1) control of basal (state 4) and ADP-stimulated (state 3) respiration, and 2) control of mitochondrial reactive oxygen species (ROS) emission.
Principle Investigator – Cortright, R.N. National Institutes of Health (1RO1DK075880-01) Impaired Acyl-CoA Synthetase-Muscle Lipid Oxidation in African American Women (AAW).
The purpose of this research is to determine if the impairment in skeletal muscle fat oxidation in African-American Women (AAW) is due to a defect in acyl-CoA synthetase (ACC), the enzyme required for activating fatty acids prior to transport and oxidation in the mitochondria and whether AAW will respond to exercise training by increasing the capacity of skeletal muscle to oxidize lipids, due in part to a normalization of ACS activity.
Principle Investigator – Cortright, R.N. National Institutes of Health (1RO1DK075880) Impaired Acyl-CoA Synthetase-Muscle Lipid Oxidation in African American Women (AAW). Funded September 2006 – 2010.
We hypothesize that the impairment in skeletal muscle fat oxidation in AAW is due to a defect in acyl-CoA synthetase, the enzyme required for activating fatty acids prior to transport and oxidation in the mitochondria. This defect likely contributes to the greater incidence of obesity and diabetes in this racial group of women. However, in lean CW, endurance exercise training stimulates the muscle's capacity to oxidize long-chain fatty acids. Our secondary hypothesis is that AAW will respond to endurance exercise training by increasing the capacity of skeletal muscle to oxidize lipids, due in part to a normalization of ACS activity. Additional recent experiments suggest a greater propensity for African-American women to generate reactive oxygen species which are linked to skeletal muscle insulin resistance. Mechanisms related to mitochondrial proton conductance are being explored including racial differences in uncoupling protein activity and the adenine nucleotide translocase antiporter (ANT1).
Principle Investigator - Cortright, R.N. National Institutes of Health (1 R15 DK061314-01). “Mitochondrial-Peroxisomal Fatty Acid Oxidation in Obesity.” Funded, September 15, 2003 - 2008.
The purpose of this research was to establish a role for peroxisomes in facilitating the oxidation of long-chain fatty acids by skeletal muscle mitochondria in the obese state. Results suggest a bioenergetic interaction between peroxisomal beta-oxidation and enhanced mitochondrial oxidation of fatty acids. This suggests a possible target for therapeutic interventions.
Principle Investigator - Cortright, R.N.
National Institutes of Health (1 R21 DK065183). “Dysregulation of Fatty-Acid Metabolism in Skeletal Muscle in African-American and Caucasian Women.” Funded, September, 2003 - 2008.
The purpose of this research was to identify the cellular sites of dysregulated fatty acid oxidation in the skeletal muscle of African American vs. Caucasian women. Results indicated a mitochondrial deficiency in lipid oxidation, predisposing this group to increased risk for obesity and diabetes. However, endurance exercise training rescued this deficiency, suggesting the need for regular exercise to reduce the risk for obesity and type II diabetes.
Kane DA, Lin CT, Anderson EJ, Kwak HB, Cox JH, Brophy PM, Hickner RC, Neufer PD, Cortright RN. Progesterone Increases Skeletal Muscle Mitochondrial H2O2 Emission in Non-Menopausal Women. Am J Physiol Endocrinol Metab. 2011 Mar;300(3):E528-35.
Kane DA, Anderson EJ, Price JW 3rd, Woodlief TL, Lin CT, Bikman BT, Cortright RN, Neufer PD. Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med. 2010 Sep 15;49(6):1082-7.
Benjamin T. Bikman, Donghai Zheng, Daniel A. Kane, Ethan J. Anderson, Tracey L. Woodlief, Jesse W. Price, G. Lynis Dohm, P. Darrell Neufer, Ronald N. Cortright. Metformin Improves Skeletal Muscle Insulin Signaling Via Altered Ampk-Ikkb Activity In Obese Rats in a Fiber-Type Dependent Manner. (Int. J. Obesity, 2010).
Benjamin T. Bikman, Tracey L. Woodlief, Robert C. Noland, Steven L. Britton, Lauren G. Koch, Robert M. Lust, G. Lynis Dohm, Ronald N. Cortright. Insulin Signaling in Rats with Low Running Capacity. Int. J. Sports Medicine, 30:631-635, 2009.
Ethan J. Anderson, Mary E. Conniff, Kristen E. Boyle, Tracey L. Woodlief, Daniel A. Kane, Chien-Te Lin, Jesse W. Price, III, Li Kang, Peter S. Rabinovitch, Hazel H. Szeto,Joseph A. Houmard, Ronald N. Cortright, David H. Wasserman, and P. Darrell Neufer. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance. J. Clin. Invest. 2009 Feb 2. pii: 37048. doi: 10.1172/JCI37048. [Epub ahead of print].