Indicators of increased ER stress and UPR in aged D2-mdx and human dystrophic skeletal muscles

Frontiers in Physiology

Physiology

Swathy Krishna¹  Hannah R. Spaulding¹  James E. Koltes¹  Joshua T. Selsby¹  Rudy J. Valentine²  John C. Quindry³ 

[1] Department of Animal Science, Iowa State University, Ames, IA, United States;Department of Kinesiology, Iowa State University, Ames, IA, United States;School of Integrative Physiology and Athletic Training, University of Montana, Missoula, MT, United States;

关键词: DMD;    mdx;    dystrophin;    unfolded protein response;    transcription factor;   

DOI  :  10.3389/fphys.2023.1152576

 received in 2023-01-27, accepted in 2023-04-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

Duchenne muscular dystrophy (DMD) is a progressive muscle disease that results in muscle wasting, wheelchair dependence, and eventual death due to cardiac and respiratory complications. In addition to muscle fragility, dystrophin deficiency also results in multiple secondary dysfunctions, which may lead to the accumulation of unfolded proteins causing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The purpose of this investigation was to understand how ER stress and the UPR are modified in muscle from D2-mdx mice, an emerging DMD model, and from humans with DMD. We hypothesized that markers of ER stress and the UPR are upregulated in D2-mdx and human dystrophic muscles compared to their healthy counterparts. Immunoblotting in diaphragms from 11-month-old D2-mdx and DBA mice indicated increased ER stress and UPR in dystrophic diaphragms compared to healthy, including increased relative abundance of ER stress chaperone CHOP, canonical ER stress transducers ATF6 and pIRE1α S724, and transcription factors that regulate the UPR such as ATF4, XBP1s, and peIF2α S51. The publicly available Affymetrix dataset (GSE38417) was used to analyze the expression of ER stress and UPR-related transcripts and processes. Fifty-eight upregulated genes related to ER stress and the UPR in human dystrophic muscles suggest pathway activation. Further, based on analyses using iRegulon, putative transcription factors that regulate this upregulation profile were identified, including ATF6, XBP1, ATF4, CREB3L2, and EIF2AK3. This study adds to and extends the emerging knowledge of ER stress and the UPR in dystrophin deficiency and identifies transcriptional regulators that may be responsible for these changes and be of therapeutic interest.

【 授权许可】

Unknown   
Copyright © 2023 Krishna, Spaulding, Koltes, Quindry, Valentine and Selsby.