The role ofmtDNA deletion mutations, electron transport system abnormalities and calorie restriction on sarcopenia

Normal aging is associated with a progressive decline in lean body mass and function, a phenomenon known as sarcopenia. Sarcopenia is a consequence of the decline in both the number and cross-sectional area of muscle fibers. The etiology of sarcopenia is clearly multifactorial, however, mitochondrial DNA (mtDNA) deletion mutations and associated electron transport system (ETS) enzymatic abnormalities have been implicated in the loss of skeletal muscle fibers with age. These ETS abnormalities include a decline in the activity of the partially mitochondrial encoded complex IV (cytochrome c oxidase; COX -) and an increase in the nuclear encoded complex II activity (succinate dehydrogenase; SDH++). Vastus lateralis, soleus and adductor longus muscles were studied in 5-, 18-, and 36-month-old male Fischer 344 x Brown Norway F1 hybrid rats. The vastus lateralis muscle, which undergoes a high degree of sarcopenia, exhibited more COX -/SDH++ fibers and associated fiber loss than the soleus and adductor longus muscles, which are more resistant to sarcopenia, suggesting a direct association between ETS abnormalities and fiber loss.;We studied the effect of early-onset calorie restriction (CR) on the skeletal muscle fiber loss and accumulation of ETS abnormalities in rectus femoris and vastus lateralis muscles. CR is the only known experimental intervention that extends lifespan and retards aging in mammals and has profound beneficial effects on skeletal muscle. Calorie restricted rats had fewer ETS abnormal muscle fibers. CR significantly reduced muscle mass loss and prevented fiber loss with age. CR reduced the generation of ETS abnormal fibers but did not effect the progression of electron transport system abnormalities. Thus, CR limited a process that ultimately results in fiber breakage and fiber loss.;Through the use of laser capture microdissection we analyzed the genotype of single COX-/SDH++ fibers of normal human subjects at different ages. We found mtDNA deletion mutations to be present in all ETS abnormal fibers in healthy aged human subjects. The deletion mutations were within the ETS abnormal segment, demonstrating the strict correlation of the COX-/SDH++ phenotype with mtDNA deletions. The deletion mutations were spread throughout the genome, resulting in the removal of many genes of the ETS complexes. The parallel accumulation of mtDNA deletion mutations, mitochondrial enzymatic deficiencies and intrafiber atrophy supports the role of mitochondrial DNA deletions in sarcopenia.