Characterization of age-associated electron transport system abnormalities and associated fiber atrophy in skeletal muscle from rhesus monkeys.

摘要

The involvement of mitochondria in the aging process has been proposed by many investigators. It is thought that the accumulation of reactive oxygen species with age may cause alterations of the mitochondrial genome, leading to mitochondrial enzymatic abnormalities and eventually cell death. The present study involved the characterization of age-associated mitochondrial abnormalities in rhesus monkey skeletal muscle.;Vastus lateralis muscle from eleven animals 11 to 34 years old was examined histologically for age-associated electron transport system (ETS) abnormalities. Two hundred serial cross-sections (totaling 1,600 microns in length) were obtained from each muscle biopsy and analyzed for mitochondrial ETS enzymatic abnormalities (COX- and/or SDH++) every 56 microns. The abundance and length of skeletal muscle fibers displaying ETS abnormal regions increased with age. ETS abnormal phenotypes were found to vary with age, with middle-aged animals primarily exhibiting the COX - phenotype while COX-/SDH++ abnormalities were more common in the muscle of old animals. Finally, the longitudinal analysis along muscle fibers identified overt decreases in fiber cross-sectional area within some ETS abnormal regions from the older animals.;In situ hybridization studies performed in ETS abnormal regions of animals of different ages using seven mitochondrial probes demonstrated an association of mitochondrial DNA (mtDNA) deletions with ETS abnormal regions. Together, these data strongly supports a causal relationship between deletions of the mitochondrial genome and the appearance of age-associated mitochondrial enzymatic abnormalities.;This study suggests that ETS abnormality formation is a continuous process. First, an increase in the abundance of ETS abnormal regions was found, these regions were of different lengths within individual animals and long ETS abnormal regions were only found in old animals. Second, the ETS abnormal phenotype varied with age such that the greatest increases in SDH activity (indicative of nuclear response) were only observed in old animals. Finally, great decreases in cross-sectional area were associated with ETS abnormal regions of old animals. These data are suggestive of a continuous process that may take many years in the rhesus monkey with the respiratory deficiencies leading to fiber atrophy and ultimately to fiber loss. MtDNA deletions, therefore, may be involved in the etiology of sarcopenia.