Vladimir Ljubicic1, Bernard J Jasmin1. 1. Department of Cellular and Molecular Medicine, Faculty of Medicine, and Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Abstract
INTRODUCTION: Metformin (MET) stimulates skeletal muscle AMP-activated protein kinase (AMPK), a key phenotype remodeling protein with emerging therapeutic relevance for Duchenne muscular dystrophy (DMD). Our aim was to identify the mechanism of impact of MET on dystrophic muscle. METHODS: We investigated the effects of MET in cultured C2 C12 muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α (PGC-1α), PPARδ, and receptor-interacting protein 140 (RIP140), as well as that of the dystrophin-homolog, utrophin A. RESULTS: In C2 C12 cells, MET augmented expression of PGC-1α, PPARδ, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC-1α and utrophin A and normalized RIP140 levels. CONCLUSIONS: In this study we identify the impact of MET on skeletal muscle and underscore the timeliness and importance of investigating MET and other AMPK activators as relevant therapeutics for DMD.
INTRODUCTION:Metformin (MET) stimulates skeletal muscle AMP-activated protein kinase (AMPK), a key phenotype remodeling protein with emerging therapeutic relevance for Duchenne muscular dystrophy (DMD). Our aim was to identify the mechanism of impact of MET on dystrophic muscle. METHODS: We investigated the effects of MET in cultured C2 C12 muscle cells and mdx mouse skeletal muscle. Expression of potent phenotypic modifiers was assessed, including peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α (PGC-1α), PPARδ, and receptor-interacting protein 140 (RIP140), as well as that of the dystrophin-homolog, utrophin A. RESULTS: In C2 C12 cells, MET augmented expression of PGC-1α, PPARδ, and utrophin A, whereas RIP140 content was reciprocally downregulated. MET treatment of mdx mice increased PGC-1α and utrophin A and normalized RIP140 levels. CONCLUSIONS: In this study we identify the impact of MET on skeletal muscle and underscore the timeliness and importance of investigating MET and other AMPK activators as relevant therapeutics for DMD.
Authors: Peter P Nghiem; Luca Bello; William B Stoughton; Sara Mata López; Alexander H Vidal; Briana V Hernandez; Katherine N Hulbert; Taylor R Gourley; Amanda K Bettis; Cynthia J Balog-Alvarez; Heather Heath-Barnett; Joe N Kornegay Journal: Yale J Biol Med Date: 2017-09-25
Authors: Rasmus Kjøbsted; Janne R Hingst; Joachim Fentz; Marc Foretz; Maria-Nieves Sanz; Christian Pehmøller; Michael Shum; André Marette; Remi Mounier; Jonas T Treebak; Jørgen F P Wojtaszewski; Benoit Viollet; Louise Lantier Journal: FASEB J Date: 2018-01-05 Impact factor: 5.191