The role of mitochondrial DNA deletion mutations in the pathogenesis of aging: Studies in rodent heart and skeletal muscle.

摘要

Aging is recognized as an intricate web of global, physiological attrition. Many of the physiologically significant, age-related changes are exhibited in non-replicative tissues such as brain, heart and skeletal muscle that rely heavily on oxidative metabolism for energy. In the aging heart and skeletal muscle, we hypothesize that mitochondrial genetic and enzymatic abnormalities, possibly due to life-long oxidative damage, may ultimately disrupt cellular processes or trigger cell death. The ensuing cellular dysfunction and loss may contribute to the structural and functional alterations recognized as aging.;Studies of mitochondrial involvement in cardiac aging were carried out in myocardial tissues from Fischer 344 x Brown Norway F 1 rats of ages 5, 18 and 36--38 months that were examined for mitochondrial genetic and enzymatic abnormalities. Mitochondrial DNA (mtDNA) deletion mutations were detected in right and left ventricular myocardium and the deletion frequency increased with age. Histochemical staining of serial myocardial sections revealed individual cardiomyocytes displaying abnormal mitochondrial enzyme activities and their frequency increased with age with localization primarily to the left ventricular (LV) subendocardium. In vivo hemodynamic measurements showed age-related changes of LV function and significant hypertrophy. The percent area of fibrosis increased from ∼10% in the 5-month-old hearts to nearly 40% in the subendocardium of the LV at 38 months. The presence of these age-related functional, structural and mitochondrial genetic and enzymatic abnormalities in the hybrid rat heart suggests the possible role of mitochondrial dysfunction, secondary to mtDNA mutations, in age-related cardiomyocyte loss and cardiac aging.;In mammalian skeletal muscle, we hypothesized that mtDNA deletions contribute to the fiber atrophy and fiber loss that cause sarcopenia, the age-related decline of muscle mass and function. We examined 82,713 rectus femoris muscle fibers from rats of ages 5, 18 and 38 months through 1,000 microns by exhaustive serial cryosectioning and histochemical staining for electron transport system enzymes. Concomitant with decreased muscle mass and fiber number, we observed increases in segmental mitochondrial abnormalities that contained specific mtDNA deletion mutations as revealed by laser capture microdissection and whole mitochondrial genome amplification. Muscle fibers harboring mtDNA deletions often displayed atrophy, splitting and oxidative damage suggesting a causal role for these mutations in sarcopenia.