Energy sensing in skeletal muscle: focus on mitochondrial metabolic adaptation

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Background: Often referred to as the "powerhouses of the cell," mitochondria have long been recognized as key producers of ATP, the cellular metabolic currency. In recent decades, however, mitochondria have increasingly been implicated in many additional cell processes, ranging from cellular calcium homeostasis to even cell death. In skeletal muscle, the energetic demands placed on the cell can fluctuate rapidly as an organism transitions between rest and exercise. Some of the purturbations in cellular redox state that occur in muscle with exercise are known to constitute a stimulus for acute alterations in mitochondrial function, as well as mitochondrial turnover and biogenesis. ******Objectives: The purpose of this research program is to determine the effects of increased energy demand associated with physical exercise on skeletal muscle mitochondrial function, with a focus on redox biology and mitochondrial energetics. It is proposed that the enzyme quinone reductase 2 (QR2) acts in a feedback loop mediated by the redox-sensitive transcription factor Nrf2, in response to physical activity, to boost mitochondrial content and activity in skeletal muscle The net result of this regulatory loop is more robust mitochondria, capable of mitigating oxidative stress and cell death, in addition to increased ATP resynthesis. In order to meet objectives, the program will address the following questions: 1) How does exercise training alter mitochondrial metabolism of specific substrates/compounds in skeletal muscle? 2) What are the mechanisms by which exercise-associated alterations in skeletal muscle mitochondrial function exert their effects on mitigating oxidative stress and cell death, in addition to increased ATP production?******Methodology: To achieve the research program objectives, we will use a combination of methodological approaches, ranging from standard molecular biology techniques, to state-of-the-art functional measurements on small skeletal muscle samples from rats (exercise-trained versus untrained) and mice (Nrf2 and QR2 null transgenic models). In so doing, the cellular localization and expression levels of both Nrf2 and QR2 will be determined in different skeletal muscle types (i.e., oxidative versus glycolytic) following exercise. The functional consequences of altered Nrf2 and QR2 content and activity in skeletal muscle following exercise will be determined. ******Impact: The expected short-term impact of this research include a better understanding of the mechanisms by which specific regulators (e.g., QR2) of mitochondrial redox biology in processes previously ignored as being fundamental to maintaining cellular energy and redox homeostasis. In the long-term, this program will expose critical regulators of mitochondrial bioenergetics which have been missing from fundamental models of regulating cell function.******