GSE167462
Metformin and leucine combination increase satellite cell abundance and extracellular matrix remodeling during disuse and recovery in aged mice
Loss of muscle mass and strength following disuse followed by impaired muscle recovery likely contribute to sarcopenia in older adults. Metformin and leucine individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor under the conditions of disuse atrophy and recovery in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET+LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice (22-24 mo). We were also interested if these muscle responses correspond to changes in satellite cells and ECM abundance. Aged mice were subjected to 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14d RL). Metformin (MET), leucine (LEU), or MET+LEU was administered via drinking water and were compared to Vehicle-treated mice. We observed that MET+LEU increased whole body grip strength, muscle specific force and satellite cell abundance during HU but did not alter muscle size during HU or RL. Moreover, MET+LEU treatment increased ECM turnover driven by a decrease in collagen IV   content during 7 and 14d RL. Transcriptome analysis revealed that MET+LEU altered Gene Set Enrichment Analysis hallmark pathways related to inflammation and myogenesis during HU. Together  , MET+LEU was able to improve muscle quality during disuse and recovery in aging possibly by increasing muscle satellite cell content and reducing excessive ECM accumulation. Overall design: 52 total samples, 4 treatment groups with 3 timepoints each. N=4/group. Reference samples used were ambulatory control or vehicle treated mice.