This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interleukin-1 (IL-1) and the inflammatory response are important for initiating structural and functional repair of muscle after damaging exercise. However, this inflammatory response must be regulated to prevent further muscle damage. We hypothesize that with aging this regulatory mechanism may fail so that muscle wasting occurs. On the other hand, inability to mount an effective inflammatory-regenerative response in some older individuals may compromise muscle adaptation to exercise. Given that the IL-1 genotype appears to influence diverse physiologic processes, we propose to determine whether there is a correlation among the muscle inflammatory response after an acute bout of resistance exercise, IL-1 abundance, and IL-1 genotype in the elderly. We hypothesize that IL-1 polymorphisms modulate muscle responses to damage and that IL-1 expression and the inflammatory response after an acute exercise bout are predictive of the adaptability of muscle of elderly individuals to chronic resistance training. We will determine whether differences in IL-1 activity contribute to the variability of muscle adaptation to exercise, particularly evident in the elderly, and may even contribute to the 'failure to thrive' phenotype that jeopardizes functional independence in the elderly.
Specific Aim 1. Determine whether there is a correlation between the muscle inflammatory response after an acute bout of resistance exercise and IL-1 abundance at the mRNA and protein levels, and if these differ across different IL-1 genotypes in the elderly. For genotyping, the five single-nucleotide polymorphisms shown to be associated with variations in IL-1 abundance or diverse biologic functions will be examined; these include IL-1A (-889), IL-1A (+4845), IL-1B (+3954), IL-1B (-511), and IL-1RN (+2018).
Specific Aim 2. Determine whether IL-1 expression and the inflammatory response after an acute exercise bout are predictive of the hypertrophic response of muscle of elderly individuals to chronic resistance training. The work of this aim will involve a subset of the individuals studied in Aim 1 with the widest range of responses. Muscle fiber size and muscle mass will be quantitated, as well as the accumulation of gene products common to AD and inclusion-body myositis (IBM), including IL-1, IL-1 converting enzyme (ICE), bAPP, amyloid-b (Ab), tumor necrosis factor-a (TNF-a), and hyperphosphorylated tau. This analysis will be combined with gene expression profiling using cDNA microarrays to determine whether different IL-1 gene expression levels are associated with specific phenotypes in exercised muscle that may predict adaptability to exercise. The goal of this project is to identify underlying molecular mechanisms that prevent muscle adaptation to exercise and potentially contribute to muscle wasting during aging. Given the pivotal role of IL-1 in the recovery of muscle from damage and the association of IL-1 polymorphisms with a variety of immune-mediated diseases, IL-1 is a strong candidate for playing a major role in the variability in muscle response to exercise with age.
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