Administrative Supplement: Mechanisms Underlying Anabolic Effects of Cyclic Compressive Loading in Muscle

This application for an Administrative Supplement is in response to the Funding Opportunity PA-18-658 entitled “Administrative Supplement for Research on Sex/Gender Influences” by the Office of Research in Women’s Health. This Supplement addresses Goal 1 of the NIH Strategic Plan for Women’s Health Research which is to increase sex differences research in basic science studies. In addition, it also addresses Objective 3.6 of the goals with higher programmatic importance, which is to study sex differences in the aging process. Specifically, this study will address the hypothesis that male and female rats will exhibit a different anabolic effect to cyclic compressive loading (CCL), a massage mimetic, during atrophy and during regrowth after atrophy with aging. Our preliminary data showed that the anabolic response to CCL is blunted in the aged male rats. Whether female rats show a similar response is currently unknown, but the literature suggests that sexual dimorphic effects are present for muscle size regulation, particularly in the aged. In the parent RO1 for which this Supplement is written, we proposed to use males and females only to compare differences in young rats and under loading conditions we have shown to be anabolic for males. We proposed that age-related changes in the extracellular matrix are responsible for the blunted response with age and will test this in Aim 1. Massage in the form of CCL also induces an anabolic response in the contralateral limb, but this effect has also only been tested in males. The underlying mechanisms for this response are unknown, but will be tested in Aim 3 of the grant application. In this current Supplemental Application we will perform CCL on female rats at the same loads as proposed for males, 0N (control), 2.5N, 4.5N, and 7N under conditions of atrophy (hind limb suspension) and during regrowth in adult (10months) and aged (31 months). Gastrocnemius muscles from both limbs will be tested for anabolic responses and serum will be collected to address the potential endocrinelike mechanisms for the cross over effect. These studies are highly significant since current literature suggests that there are sex related differences not only in the protein synthesis response to exercise, but also in the regulation of the extracellular matrix, particularly in the aged, which is important in force transmission during massage. These studies will inform whether the application of CCL for muscle maintenance needs to be personalized for the different sexes.