Non-communicable diseases, such as heart disease, stroke, cancer and diabetes, kill 38 million people worldwide each year. These diseases are caused/exacerbated by an accumulation of damaged/dysfunctional mitochondria in vital tissues/organs. Research in the PI's and many other laboratories show that regular exercise improves mitochondrial function and is the most powerful intervention for the prevention and treatment of non-communicable diseases. However, the molecular mechanisms underlying the benefits of exercise remain largely unknown, hindering our ability to optimize exercise intervention and develop more effective therapeutics. Autophagy, a conserved cellular degradation process for aggregated proteins and damaged organelles is activated in skeletal muscle by exercise; however, the regulation and functional role of mitophagy, a specific autophagic clearance process for mitochondria, in skeletal muscle by exercise training is poorly understood. We developed a novel mitochondrial reporter gene, pMitoTimer, for quantification of mitochondrial oxidative stress and mitophagy in vivo. Using this novel tool, we have recently shown that a single bout of exercise induces mitochondrial oxidative stress and mitophagy in skeletal muscle, preceded by a transient activation of the nutrient/energy sensor AMP-activated protein kinase (AMPK), autophagy protein unc-51 like autophagy activating kinase 1 (Ulk1) and mitochondrial fission regulator dynamin-related protein 1 (Drp1), where both Ulk1 and Drp1 are known to be required for mitophagy. We further demonstrated in muscle-specific dominant negative and constitutive active AMPK transgenic mice (dnAMPK and caAMPK, respectively) that activation of Ulk1, but not that of Drp1, is caused by AMPK activation. These findings along with previous findings of the role of AMPK-Ulk1 in non-muscle cells serve as scientific foundation for this proposal. We hypothesize that exercise-induced activation of AMPK and Ulk1 along with Drp1-1 mediated mitochondrial fission promotes mitophagy, hence improved mitochondrial quality, and contractile and metabolic adaptations. To test this hypothesis, we propose the following specific aims: 1) To dissect the role of AMPK in exercise-induced mitophagy in skeletal muscle in vivo. 2) To ascertain the role of Ulk1 and Drp1 in exercise-induced mitophagy in skeletal muscle in vivo. 3) To define the functional role of mitophagy in exercise training-induced adaptations. The proposed studies will address one of the most important questions in muscle biology and exercise physiology. The results, whether accepting or refuting the hypothesis, will significantly improve our mechanistic understanding of exercise training-induced mitochondrial quality control and functional adaptation in skeletal muscle with great potential impact on future research of health benefits of exercise.
Mitochondrion is the powerhouse of the cell. Accumulation of bad mitochondria in the cells in our body causes many common diseases, and regular exercise improves the quality of mitochondria with profound benefits for health. However, how does regular exercise get rid of bad mitochondria is largely unknown. We have obtained evidence to show that a nutrient/energy sensor and the factors controlled by it are involved in removing bad mitochondria in muscle after exercise. Here, we will use the state-of-the-art technologies to dissect this important process, which could lead to new, effective therapeutics for many chronic diseases.
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