Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease

Muscle mitochondrial content is tightly regulated, and requires the express ion of both nuclear and mitochondrial genes. In addition, muscle mitochondr ial content is a major determinant of aerobic exercise capacity in healthy subjects. The current study was designed to test the hypothesis that in hea lthy humans, muscle mitochondrial DNA (mtDNA) content is correlated with ci trate synthase activity (a representative nuclear-encoded mitochondrial enz yme) and aerobic exercise capacity as defined by whole-body peak oxygen con sumption ((V) over dot O-2). Furthermore, it was postulated that these rela tionships might be altered with disease. Twelve I; healthy and five paraple gic subjects underwent exercise testing and vastus lateralis muscle biopsy sampling. An additional ten healthy subjects and eight patients with unilat eral peripheral arterial disease (PAD) underwent exercise testing and gastr ocnemius muscle biopsy sampling. Citrate synthase activity and mtDNA conten t were positively correlated in the vastus lateralis muscles from the healt hy subjects. This relationship was similar in muscle from paraplegic subjec ts. mtDNA content was positively correlated with peak (V) over dot O-2 in t he healthy subjects and in the paraplegic subjects in whom peak (V) over do t O-2 had been elicited by functional electrical stimulation of the muscle. In contrast, the PAD subjects demonstrated higher mtDNA contents than woul d have been predicted based on their claudication-limited peak (V) over dot O-2 Thus, in healthy humans there are strong relationships between muscle mtDNA content and both muscle citrate synthase activity and peak (V) over d ot O-2. These relationships are consistent with coordinant nuclear DNA and mtDNA expression, and with mitochondrial content being a determinant of aer obic exercise capacity. The relationships seen in healthy humans are quanti tatively similar in paraplegic patients, but not in patients with PAD, a di sease which is associated with a metabolic myopathy. The relationships betw een mtDNA content, mitochondrial enzyme activities and exercise capacity pr ovide insight into the physiologic and pathophysiologic regulation of muscl e mitochondrial expression.