Endurance exercise induces an increase in skeletal muscle respiratory capacity that is mediated by an increase in mitochondria. The goal of this research is to discover the mechanisms by which exercise induces an increase in muscle mitochondria. Functional recognition sites for the transcription factors NRF-1 and/or NRF-2 have been identified in the promoters of nuclear genes that encode a number of the subunits of respiratory chain enzyme complexes, mitochondrial matrix enzymes, and mtDNA transcription and replication factors. It is our hypothesis that NRF-1 and NRF-2 play important roles in mediating the exercise-induced increase in muscle mitochondria.
Our aims relative to this hypothesis are to determine whether a bout of exercise results in increases in NRF-1 and NRF-2 mRNA levels and protein concentrations in muscle. As a next step, we will test the hypothesis that an increase in NRF-1 induces an increase in mitochondrial biogenesis by overexpression of NRF-1 in muscle. Another question of major interest that we plan to address is; which of the perturbation in intracellular homeostasis during exercise serves as the signal that initiates induction of the adaptive increase in muscle mitochondria? Relative to this question, our aims are: 1) To test the hypothesis that the increase in cAMP that occurs in contracting muscle serves as the signal that initiates the events leading to an increase in mitochondria. 2) To evaluate the hypothesis that a decrease in phosphorylation potential induces the increase in mitochondrial biogenesis. 3) To test the hypothesis that an increase in intracellular Ca2+ induces an increase in mitochondrial biogenesis. 4) To test the hypothesis that a change in redox state that results in an increase in DNA binding activity of a number of transcription factors by reduction of cysteine residues, stimulates mitochondrial biogenesis. 5) To evaluate the hypothesis that activation of MAP kinases mediates the stimulation of mitochondrial biogenesis. Exercise deficiency is a serious public health problem. It plays a major role in development of abdominal obesity, NIDDM, ISCHD, and the decline in cardiovascular and muscle function. Many people who would benefit are unwilling or unable to exercise. Information obtained form this research may make it possible to mimic some of the beneficial effects of exercise through pharmacological or gene therapy intervention. Increasing muscle mitochondria using such approaches could compensate for mitochondrial mutations that contribute to muscle dysfunction as well as pathophysiological effects of inactivity in patients with heart failure or advanced ISCHD.
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