ROLE OF DIETARY RESTRICTION-INDUCED METABOLIC ALTERATIONS IN SARCOPENIA

University Of Wisconsin-Madison, Madison WI

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Abstract

The loss of skeletal muscle mass with aging (sarcopenia) is important to public health due to its effects on the[unreadable] functional capacity of older adults. The rhesus monkey provides an outstanding model to study sarcopenia and the[unreadable] effect of dietary restriction (DR) on its progression in primates. We hypothesize that DR induces an altered state[unreadable] of mitochondrial energy metabolism that is central to the retardation of aging, and that this "metabolic shift"[unreadable] is responsible for slowing the rate of sarcopenia in DR animals.[unreadable] Specific Aim 1: To generate transcriptional and proteomic profiles of the effects of age and DR on skeletal[unreadable] muscle. This is a longitudinal study on vastus lateralis (VL) biopsies obtained from Group 1 monkeys in 1994 and[unreadable] year one of the study. Affymetrix human microarray data will be mined to probe functional groups of genes central[unreadable] to energy metabolism with a focus on genes involved in mitochondrial function. Comparative proteomic analysis of[unreadable] mitochondria from the same biopsies and Group 2 animals, using 2D electrophoresis and mass spectrometry, will[unreadable] further define mitochondrial status. Western blot analysis will confirm the results of the microarray work and[unreadable] examine the effect of age and DR on specific proteins involved in metabolic regulation and cell signaling.[unreadable] Specific Aim 2: To identify critical ages at which phenotypes of sarcopenia emerge in the rhesus monkey[unreadable] and to define the effect of DR on the progression of muscle changes with age. Analyses of changes in[unreadable] quadriceps muscles from male and female Wisconsin National Primate Research Center (WNPRC) colony and PPGsupported[unreadable] monkeys collected at necropsy, as well as biopsy samples from control and DR monkeys, combined with[unreadable] longitudinal DXA and MRI muscle mass estimations from live monkeys over time, will define specific ages at which[unreadable] muscle mass loss, muscle fiber loss, muscle fiber atrophy and mitochondrial enzyme abnormalities present in aging[unreadable] rhesus monkeys.[unreadable] Specific Aim 3: To quantitate mtDNA deletion mutations and abundance of specific mRNAs in single[unreadable] microdissected sections of muscle fibers. Laser capture microdissection will be used to select, from DR and[unreadable] control monkeys, single vastus lateralis muscle fibers exhibiting ETS normal and ETS abnormal phenotypes. The[unreadable] abundance of WT and mtDNA deletion mutations as well as the levels of selected mRNAs, the abundance of which[unreadable] change with age and/or diet (identified in Aim 1), will be quantified.