The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect. Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and adipose tissue mobilization. We hypothesize that membrane potential modulation, due to KATP channel opening in response to a physiological workload, limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Conversely, disruption of KATP channel function would result in exaggerated cellular calcium turnover, causing increased energy consumption and activation of calcium/calmodulin dependent protein kinase (Ca2+/CaMKII). We propose, that induction of CaMKII triggers both Akt-dependent production and Ca2+- dependent secretion of a signaling peptide - musclin. This peptide is known for its ability to modulate clearance of atrial natriuretic peptide (ANP) - a potet activator of lipolysis. In this way, musclin signaling could translate increased activity related energy consumption into adipose tissue mobilization. The goal of this project is to directly study the molecular mechanism of KATP channel control of activity- related energy consumption and the mechanism of consequent adipose tissue mobilization and body weight reduction. The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related diseases.
Obesity is occurring at epidemic rates and has exceeded 30% of the U.S. population. Yet despite the medical, social and economic impact of obesity, only a few therapeutic options with limited success rates are currently available. This application addresses the novel hypotheses that metabolism-sensing KATP channels are important regulators of bodily energy balance and weight management, due to the effect of their function on muscle energy efficiency and mobilization of fat, and are potential targets for prevention and treatment of obesity.
|Sierra, Ana; Subbotina, Ekaterina; Zhu, Zhiyong et al. (2016) Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin. Biochem Biophys Res Commun 471:129-34|
|Subbotina, E; Koganti, S R K; Hodgson-Zingman, D M et al. (2016) Morpholino-driven gene editing: A new horizon for disease treatment and prevention. Clin Pharmacol Ther 99:21-5|
|Gao, Zhan; Sierra, Ana; Zhu, Zhiyong et al. (2016) Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury. PLoS One 11:e0151337|
|Koganti, Siva Rama Krishna; Zhu, Zhiyong; Subbotina, Ekaterina et al. (2015) Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis. Mol Ther 23:707-16|
|Subbotina, Ekaterina; Sierra, Ana; Zhu, Zhiyong et al. (2015) Musclin is an activity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci U S A 112:16042-7|
|Rasmussen, Tyler P; Wu, Yuejin; Joiner, Mei-ling A et al. (2015) Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc Natl Acad Sci U S A 112:9129-34|
|Zhu, Zhiyong; Sierra, Ana; Burnett, Colin M-L et al. (2014) Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. J Gen Physiol 143:119-34|
|Sierra, Ana; Zhu, Zhiyong; Sapay, Nicolas et al. (2013) Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. J Biol Chem 288:1568-81|