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C1improves motor performance and muscle pathology via activating AMPK-PGC-1α in a mouse model of Duchenne muscular dystrophy

ABSTRACT: Objectives: This study was conducted to investigate the protective effect and intervention mechanism of C1 (a selective AMPK activator) on muscle damage in mice with Duchenne muscular dystrophy (DMD). Methods: We administered C1 (18 mg/kg and 54 mg/kg) to 10-week-old male DMD mice for 8 weeks. A series of behavioral tests were carried out to assess motor ability. Skeletal muscle samples were subjected to pathological analysis, western blot and proteomic analysis to explore the different protein networks associated with muscle pathology. Compound C, an AMPKα inhibitor, has been used as a negative control for follow-up experiments to verify the efficiency of C1 on AMPK activation. Key findings： C1 treatment significantly enhanced motor function and reduced muscle fibrosis and inflammation in DMD mice. We then found that C1 activated the AMPKα/PGC-1α signaling pathway, increasing ATP levels and mitochondrial DNA copy number in DMD mice. These improved effects on mitochondrial function were reversed by Compound C. In addition, Gastrocnemius muscle proteomics showed that C1 attenuated oxidative stress damage and improved muscle structural development. Conclusion: Collectively, C1 alleviates muscle damage in DMD mice by activating AMPKα to improve mitochondria.

ORGANISM(S): Mus Musculus

SUBMITTER: Xifei Yang

PROVIDER: PXD041297 | iProX | Mon Apr 03 00:00:00 BST 2023

REPOSITORIES: iProX

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Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze 23-month old female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were housed under standard conditions, 3 mice per cage, with food and water ad libitum. Mice were injected intraperitoneally with 5-Aminoimidazole-4-carboxamide-1-a-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) dissolved in saline, 500 mg/kg/day for 3 (ACR3), 7 (ACR7) or 14 (ACR14) days or saline vehicle, for 3 (CTR) days. Thirty-three days after the final injection animals were deeply anesthetized with isofluorane and perfused transcardially with 0.9% NaCl solution. The gastrocnemius muscle and Hippocampus were quickly removed, frozen on dry ice and stored at M-bM-^HM-^R80 M-BM-0C for RNA isolation and microarray analysis.

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C1improves motor performance and muscle pathology via activating AMPK-PGC-1α in a mouse model of Duchenne muscular dystrophy

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