A pandemic in obesity-related metabolic diseases has increased at an alarming rate over the last two decades. Lifestyle changes promote limited success for long-term weight management, while many medical interventions have side effects. Reduction in energy efficiency might provide an alternative approach to promote weight loss. As skeletal muscle is an organ with large mass and metabolic demand, energy inefficiency in skeletal muscle would be predicted to promote substantial increase in whole body energy expenditure. Studies in membrane vesicles suggest that energy efficiency of sarco/endoplasmic reticulum (SR/ER) Ca2+-ATPase (SERCA) pump may be modulated by composition of SR phospholipids. In this application, we propose to investigate the role of phosphatidylethanolamine (PE) methylation in regulating muscle energy efficiency. PE methylation is catalyzed by an enzyme PE methyltransferase (PEMT), and mice with whole body deletion of PEMT are protected from diet-induced obesity. We discovered that skeletal muscles from PEMT knockout mice have elevated metabolic rate, which was likely promoted by a reduction in SERCA energy efficiency. We hypothesize that PE methylation deficiency reduces SERCA energy efficiency through its effects on skeletal muscle SR phospholipid composition.
Aim 1 : With tissue-specific inactivation of PEMT, we will determine how PE methylation deficiency affects cellular Ca2+ handling to increase skeletal muscle energy expenditure.
Aim 2 : In multiple experimental models, we will determine whether alterations in muscle SR phospholipids would be sufficient to induce changes in resting metabolic rate and propensity for diet-induced obesity.
Aim 3 : We will derive mechanical efficiency (?) of contracting muscles with PE methylation deficiency. We will also examine whether inactivation of PEMT would augment the anti-obesogenic effect of regular exercise.
Obesity and its associated co-morbidities are major public health problems. In United States, 70.9% of men and 61.9% of women are overweight. Findings from these studies may lead to novel therapeutic approaches to the treatment of the obesity-related diseases.
| Anderson, Ethan J; Vistoli, Giulio; Katunga, Lalage A et al. (2018) A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress. J Clin Invest 128:5280-5293 |
| Ferrara, Patrick J; Verkerke, Anthony R P; Brault, Jeffrey J et al. (2018) Hypothermia Decreases O2 Cost for Ex Vivo Contraction in Mouse Skeletal Muscle. Med Sci Sports Exerc 50:2015-2023 |
| Ferhat, Maroua; Funai, Katsuhiko; Boudina, Sihem (2018) Autophagy in Adipose Tissue Physiology and Pathophysiology. Antioxid Redox Signal : |
| Park, Hongsuk; He, Anyuan; Tan, Min et al. (2018) Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. J Clin Invest : |
| Johnson, Jordan M; Ferrara, Patrick J; Verkerke, Anthony R P et al. (2018) Targeted overexpression of catalase to mitochondria does not prevent cardioskeletal myopathy in Barth syndrome. J Mol Cell Cardiol 121:94-102 |
| Heden, Timothy D; Ryan, Terence E; Ferrara, Patrick J et al. (2017) Greater Oxidative Capacity in Primary Myotubes from Endurance-trained Women. Med Sci Sports Exerc 49:2151-2157 |
