IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties

Abstract

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-β) and TGF-β receptor II (TGF-βr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-β signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-βr2 deleted in skeletal muscle (SM TGF-βr2−/−) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-β signaling activator, this study further revealed an essential role of intrinsic TGF-β signaling in regulating muscle cell to express inflammation-related molecules including H-2Kb, H2-Eα, TLR3, and special myokines. TGF-β signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-β signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR–IRE1α–p38 MAPK pathway.

Higher systemic immune-inflammation index is associated with sarcopenia in individuals aged 18–59 years: a population-based study

“…With age, circulating levels of inflammatory markers such as interleukin-6 (IL-6), C-reactive protein (CRP), tumour necrosis factor α (TNF-α), and IL-1β significantly increase and are directly related to decreased muscle mass and strength 67 – 69 . IL-6 is involved in the regulation of myoprotein turnover and is considered to be a catabolic cytokine 70 , 71 . Inflammation can also indirectly reduce the concentration of growth hormone (GH) and IGF-1 in the body, which can have a negative impact on skeletal muscle 72 , 73 , inducing the occurrence of sarcopenia.…”

Exploration of Potential Target Genes of miR-24-3p in Chicken Myoblasts by Transcriptome Sequencing Analysis

“…We have found no previous studies on the relationship between Salmonella infection and skeletal muscle development. The TGF-β signaling pathway was proven to be a key regulator of skeletal muscle growth [ 50 , 51 ]. Studies provided evidence that the MAPK signaling pathway played a significant role in myoblast development.…”