Location: Forage-animal Production Research
Project Number: 5042-32630-004-012-R
Project Type: Reimbursable Cooperative Agreement
Start Date: Feb 1, 2025
End Date: Jan 31, 2026
Objective:
Determine the mechanism, bacteria, and metabolites through which the cecal contents of exercise-trained mice is able to ameliorate skeletal muscle atrophy induced by disuse. The hypothesis is that the gut bacterial lysine degradation products, pipecholic acid and succinic acid, active mTORC1. If true, technologies can subsequently be developed to help sedentary patients maintain muscle mass. The knowledge can also subsequently be applied to deposition of muscle mass in meat production.
Approach:
Specific Aim 1. Determine how the transfer of cecal contents from exercised-trained mice is able to ameliorate skeletal muscle atrophy. Based on our preliminary data, we hypothesize the transfer of cecal contents from exercise-trained mice will reduce muscle atrophy of recipient mice by stimulating myofiber protein synthesis via mTORC1 activation. To test this hypothesis, adult female and male mice will receive cecal content from either sedentary or exercise-trained mice prior to and during 10 days of unilateral hind limb immobilization; the contralateral leg will serve as control. The impact of cecal transfer on myonuclear heterogeneity during atrophy will be assessed using single-nuclear RNA-seq of FACS-isolated GFP+ myonuclei from the HSA-rtTA; TetO-H2B-GFP (HSA-GFP) mouse.
Specific Aim 2. Determine if a probiotic containing candidate bacterial species is able to ameliorate skeletal muscle atrophy. Based on our metagenomic analysis, we hypothesize a probiotic supplement containing Duncaniella muris and/or Akkermansia muciniphila will ameliorate muscle atrophy induced by hind limb immobilization. To test this hypothesis, adult female and male C57BL/6J mice will be administered by gavage the proposed probiotic supplement for 17 days with the last 10 days subjected to unilateral hind limb immobilization. Muscle atrophy and function will be assessed as describe in Aim 1.
Specific Aim 3. Determine if administration of microbial-derived metabolites is able to ameliorate skeletal muscle atrophy. Based on metabolomic analysis, we hypothesize the administration of pipecolic acid and/or succinate will significantly reduce muscle atrophy induced by hind limb immobilization. To test this hypothesis, adult female and male C57BL/6J mice will be administered via drinking water pipecolic acid (200 mg/kg) and/or succinate (100 mg/kg) during 10 days of unilateral hind limb immobilization. Muscle atrophy and function as will be assessed as describe in Aim 1.
The Cooperator will be responsible for project management, hiring and supervision of temporary personnel, all aspects of animal acquisition and care, and muscle atrophy assays.
ARS will prepare probiotic cultures and provide analytical support.