Mitochondria are organelles within cells that are largely responsible for converting metabolic fuel into a form of energy that can be used by the rest of the cell. The long term objective of this research is to understand the role of mitochondrial function/dysfunction may play in the etiology of metabolic disease. The overriding hypothesis of this project is that the nutritional imbalance in skeletal muscle created by an oversupply of metabolic substrates ("over nutrition", particularly from high fat diets) coupled with low energy demand (sedentary lifestyle) increases the propensity for mitochondrial hydrogen peroxide generation and emission, representing the potential primary factor for the decrease in insulin sensitivity associated with diet-induced obesity. Using a novel approach to study mitochondrial function in human myofibers in situ, the Specific Aims of this project are: 1) to determine the impact of obesity on the regulation of mitochondrial function, cellular redox balance and insulin sensitivity in skeletal muscle of sedentary lean verses obese young adults;2) to determine how high calorie/high fat intake in lean humans acutely and/or chronically affects mitochondrial function, cellular redox balance and insulin sensitivity;3) to determine whether increased physical activity restores redox balance and insulin sensitivity in obese individuals or in lean individuals consuming a high calorie/high fat diet;and 4) to investigate in cultured human primary myotubes whether mitochondrial ROS emission is a primary cause of lipid-induced insulin resistance.

Public Health Relevance

This research seeks to identify the mechanism(s) by which metabolic imbalance caused by over nutrition and physical inactivity leads to altered mitochondrial function and insulin resistance in skeletal muscle of humans. This is highly significant, as a fundamental understanding of the causes of insulin resistance is necessary in order to devise adequate preventive measures and treatments to reduce the health and financial impact of the obesity and diabetes epidemics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Laughlin, Maren R
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East Carolina University
Other Domestic Higher Education
United States
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Ryan, Terence E; Brophy, Patricia; Lin, Chien-Te et al. (2014) Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. J Physiol 592:3231-41
Bamman, Marcas M; Cooper, Dan M; Booth, Frank W et al. (2014) Exercise biology and medicine: innovative research to improve global health. Mayo Clin Proc 89:148-53
Rogers, Carlyle; Davis, Barbara; Neufer, P Darrell et al. (2014) A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids. Free Radic Biol Med 67:330-41
Jackson, Kathryn C; Gidlund, Eva-Karin; Norrbom, Jessica et al. (2014) BRCA1 is a novel regulator of metabolic function in skeletal muscle. J Lipid Res 55:668-80
Perry, Christopher G R; Kane, Daniel A; Lanza, Ian R et al. (2013) Methods for assessing mitochondrial function in diabetes. Diabetes 62:1041-53
Fisher-Wellman, Kelsey H; Neufer, P Darrell (2012) Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab 23:142-53
Kwak, Hyo-Bum; Thalacker-Mercer, Anna; Anderson, Ethan J et al. (2012) Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes. Free Radic Biol Med 52:198-207
Kane, Daniel A; Lin, Chien-Te; Anderson, Ethan J et al. (2011) Progesterone increases skeletal muscle mitochondrial H2O2 emission in nonmenopausal women. Am J Physiol Endocrinol Metab 300:E528-35
Perry, Christopher G R; Kane, Daniel A; Lin, Chien-Te et al. (2011) Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle. Biochem J 437:215-22
Boyle, K E; Canham, J P; Consitt, L A et al. (2011) A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals. J Clin Endocrinol Metab 96:775-81

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