Dietary Restriction, mt DNA Abnormalities and Aging

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DESCRIPTION: (Verbatim from application) 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 skeletal muscle, we hypothesize that mitochondrial genetic and enzymatic abnormalities, possibly secondary to life-long oxidative damage, may ultimately disrupt cellular processes or trigger cell death. The ensuing skeletal muscle fiber dysfunction or loss may contribute to sarcopenia, the age-related loss of skeletal muscle mass and function. We are addressing, by the in situ analyses of skeletal muscle from aged rodents, the question of the biological impact of mitochondrial abnormalities. Our studies suggest a specific sequence of events linking mtDNA deletions to sarcopenia. Concomitant with decreased muscle mass and fiber number, we have observed increases in segmental mitochondrial abnormalities that contain specific rntDNA deletion mutations as revealed by laser capture microdissection and whole mitochondrial genome amplification. Muscle fibers harboring mtDNA deletion mutations often display atrophy, splitting and oxidative damage demonstrating a cellular impact of these abnormalities. These correlations suggest a causal role for mtDNA deletion mutations in sarcopenia. The aims of the present proposal are four-fold: 1) characterize ETS abnormalities, fiber atrophy, fiber splitting and oxidative damage during the progression of sarcopenia in selected rat muscles; 2) ascertain the cellular impact of age-associated ETS abnormal segments by gene expression profiling of laser-capture microdissected muscle fibers 3) Assess the effect of early- and adult-onset caloric restriction on the progression of sarcopenia and the accumulation of mitochondrial abnormalities in selected muscles of F344BNF1 rats; 4) determine whether mitochondrial genomes harboring deletion mutations are causally related to age-associated ETS abnormalities and subsequent cellular impact. The outcome of this work will shed additional light on the biological significance of these mutations and the effects they have on the age-related changes in muscle physiology and structure.