Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease

Abstract

Skeletal muscle is the most abundant tissue in the human body and can adapt its mass as a consequence of physical activity, metabolism, growth factors, and disease conditions. Skeletal muscle contains an extensive network of endoplasmic reticulum (ER), called sarcoplasmic reticulum, which plays an important role in the regulation of proteostasis and calcium homeostasis. In many cell types, environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen that ultimately leads to ER stress. To alleviate the stress and restore homeostasis, the ER activates a signaling network called the unfolded protein response (UPR). The UPR has three arms, which regulate protein synthesis and expression of many ER chaperone and regulatory proteins. However, the role of individual UPR pathways in skeletal muscle has just begun to be investigated. Recent studies suggest that UPR pathways play pivotal roles in muscle stem cell homeostasis, myogenic differentiation, and regeneration of injured skeletal muscle. Moreover, markers of ER stress and the UPR are activated in skeletal muscle in diverse conditions such as exercise, denervation, starvation, high fat diet, cancer cachexia, and aging. Accumulating evidence also suggests that ER stress may have important roles in the pathogenesis of inflammatory myopathies and genetic muscle disorders. The purpose of this review article is to discuss the role and potential mechanisms by which ER stress and the individual arms of the UPR regulate skeletal muscle formation, plasticity, and function in various physiological and pathophysiological conditions. K E Y W O R D Satrophy, ER stress, myogenesis, skeletal muscle, UPR

Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy

“…A sensitive increase in temperature (40-46°C) can cause protein unfolding, entanglement, and aggregation, and further induce ER stress [27]. ER stress was induced with increased eIF2α phosphorylation and XBP1 splicing, resulting in the increased expression of GADD34, CHOP and BiP genes [14, 28]. We obtained similar ER stress responses in heat-treated 16HB140 cells.…”

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

“…In contrast with rodent data, here we have demonstrated that a short training program based on repeated high‐intensity exercise reduced the SLN protein levels in vastus lateralis despite eliciting much less total energy expenditure than the 4‐day walking intervention. A principal difference between prolonged walking and repeated 30‐second all‐out sprints is the marked metabolic disturbances evoked by the sprints, which cause substantial lactic acidosis, oxidative stress, and sarcoplasmic reticulum stress . Endoplasmic reticulum stress reduces SLN expression in C2C12 cells .…”

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

“…Protein turnover and removal of misfolded and poly-ubiquitinated proteins are predominately accomplished by 2 degradation machineries, the ubiquitin-proteasome system (UPS) as well as the autophagy and lysosome system [1–3]. Dysfunction of either of these proteolytic machineries has been implicated in the onset and progression of striated muscle as well as neurodegenerative diseases [4,5,6]. In this context, point mutations in VCP/p97 (valosin containing protein) were shown to cause inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS).…”