(Verbatim from the application) One of the most serious problems of mobility impairment is the tendency of old adults to fall. Falls account for almost 90 percent of all fractures in the elderly. The limitations in performing activities of daily living and falls are undoubtedly associated with alterations on postural muscles. Postural muscles are concerned with steadying a segment of the body on another in standing. This muscle subgroup exhibits a high content of slow muscle fibers. In the soleus muscle of many adult mammals the proportion of this type of fiber approaches 100 percent (more than 80 percent in humans). Although the crucial role in posture, the mechanical properties and the molecular mechanisms involved in single intact slow fibers contraction in the elderly or animal models of aging have not been explored. Unfortunately the information about age-related changes in fast-twitch fibers cannot be extrapolated to slow fibers due to substantial physiological, structural and biochemical differences between the two fiber subtypes. The hypothesis of this proposal is that the decrease in dihydropyridine receptor (DHPR) gene expression in type-1 fibers results in a decline in skeletal muscle force with aging. A lower number of DHPR renders a significant number of RyR1 unlinked and unable to be activated by sarcolemmal depolarization, leading to a substantial decline in sarcopasmic reticulum Ca2+influx and contractile force in aging slow-twitch muscles. This hypothesis will be assessed using the following specific aims: (1) To determine whether the decline in single skeletal muscle fiber contractility is associated with alterations in peak intracellular calcium concentration in single slow-twitch (type 1) muscle fibers from young (7months), middle-age (14), and old (28) C57BL/6 mice. (2) To establish whether the age-related impairment in type-1 fiber contractility results from a reduction in sarcoplasmic reticulum Ca2+ release. (3) To determine whether the age-related decline in functionally monitored DHPR is associated with a decrease in DHPR gene expression measured in the same type-1 single muscle fiber or whole soleus muscle, and (4) To define whether alterations in DHPR and/or RyR1 expression in slow muscle from aging mice results from a decline in nuclear transcriptional activity of DHPR alpha1, alpha2, beta, gamma and delta subunits and/orRyR1 DNA.
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