J.J. Petrocelli, Z.S. Mahmassani, J.A. Montgomery, P.T. Reidy, D.K. Fix, A.I. McKenzie, N.M. de Hart, M.J. Drummond

University of Utah, Salt Lake City, UT

The hospitalization of older adults is predicted to increase within the next 15 years. The aging population is growing, and the majority will deal with prolonged and incomplete muscle and strength recovery. An inability to fully regain lost muscle after inactivity drives the diminished response to rehabilitation and is accompanied by muscle fibrosis. PURPOSE: Thus, the purpose of this study was to investigate how combination therapy of metformin and leucine effects muscle recovery following disuse in aged mice. METHODS: Aged mice (22-24 mo) underwent 14 days of hindlimb unloading (HU) then 7 or 14 days of recovery. Age and weight-matched mice did not undergo HU and were used as ambulatory comparators (AMB). Mice assigned to each time point received either standard drinking water (control), water with metformin (MET), or water with metformin and leucine (MET+LEU) throughout the HU and recovery period. Hindlimb muscles were dissected, snap frozen, sectioned and stained for histological analysis. RESULTS: HU decreased gastrocnemius and soleus muscle mass and fiber cross sectional area in all groups vs. AMB (P<0.05). After 7 days of recovery gastrocnemius muscle mass of control mice was still decreased vs. AMB (P=0.006) while MET+LEU mice were not different vs. AMB (P=0.085). Following HU, MET+LEU mice had increased Pax7+ cells in gastrocnemius vs. control (P=0.05); after 7 days of recovery in soleus there were also increased Pax7+ cells (P=0.019) compared to control. Additionally, after 7 days of recovery gastrocnemius of MET+LEU mice had increased central nuclei compared to control (P=0.015). Lastly, after HU and throughout the recovery period, MET+LEU mice had increased collagen turnover (main effect P<0.001) and decreased total fibrosis vs. control (Tukey’s post-hoc P=0.033). CONCLUSION: Metformin-leucine treatment improves recovery in aged mice following muscle disuse by promoting regenerative cells and decreasing fibrosis but does not affect fiber size.

Support provided by University of Utah Sports Medicine & Science Grant.

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