Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis

Neurobiology of Disease

Shogo Wada¹  Peter Hespel²  Bertrand Léger²  Aaron P. Russell²  Glenn D. Wadley³  Takashi Ushida³  Gianni Soraru⁴  Séverine Lamon⁴  Lodovica Vergani⁵  Romain Cartoni⁵  Corrado Angelini⁶  M. Benjamin Hock⁶  Takayuki Akimoto⁶  Anastasia Kralli⁷ 

[1] Correspondence to: A.P. Russell, Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia. Fax: [phone].;Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 3125 Burwood, Australia;Clinique romande de réadaptation, 1951 Sion, Switzerland;Department of Chemical Physiology, The Scripps Research Institute,92037 La Jolla, USA;Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo, 113‐0033 Tokyo, Japan;Neurosciences Department, University of Padua, 35129 Padua, Italy;Research Centre for Exercise and Health, Faculty of Kinesiology and Rehabilitation Sciences, K.U. Leuven, B-3001 Leuven, Belgium;

关键词: Peroxiome proliferator activator receptor γ co-activator‐1;    Mitofusin;    Skeletal muscle;    MicroRNA;    ALS (amyotrophic lateral sclerosis);   

DOI  :  

来源: DOAJ

【 摘 要 】

Skeletal muscle mitochondrial dysfunction is believed to play a role in the progression and severity of amyotrophic lateral sclerosis (ALS). The regulation of transcriptional co-activators involved in mitochondrial biogenesis and function in ALS is not well known. When compared with healthy control subjects, patients with ALS, but not neurogenic disease (ND), had lower levels of skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA and protein and estrogen-related receptor-α (ERRα) and mitofusin-2 (Mfn2) mRNA. PGC-1β, nuclear respiratory factor-1 (NRF-1) and Mfn1 mRNA as well as cytochrome C oxidase subunit IV (COXIV) mRNA and protein were lower in patients with ALS and ND. Both patient groups had reductions in citrate synthase and cytochrome c oxidase activity. Similar observations were made in skeletal muscle from transgenic ALS G93A transgenic mice. In vitro, PGC-1α and PGC-1β regulated Mfn1 and Mfn2 in an ERRα-dependent manner. Compared to healthy controls, miRNA 23a, 29b, 206 and 455 were increased in skeletal muscle of ALS patients. miR-23a repressed PGC-1α translation in a 3′ UTR dependent manner. Transgenic mice over expressing miR-23a had a reduction in PGC-1α, cytochome-b and COXIV protein levels. These results show that skeletal muscle mitochondrial dysfunction in ALS patients is associated with a reduction in PGC-1α signalling networks involved in mitochondrial biogenesis and function, as well as increases in several miRNAs potentially implicated in skeletal muscle and neuromuscular junction regeneration. As miR-23a negatively regulates PGC-1α signalling, therapeutic inhibition of miR-23a may be a strategy to rescue PGC-1α activity and ameliorate skeletal muscle mitochondrial function in ALS.

【 授权许可】

Unknown