Abstract
Cellular stress has been considered a relevant pathogenetic factor in a variety of human diseases. Due to its primary functions by means of contractility, metabolism, and protein synthesis, the muscle cell is faced with continuous changes of cellular homeostasis that require rapid and coordinated adaptive mechanisms. Hence, a prone susceptibility to cellular stress in muscle is immanent. However, studies focusing on the cellular stress response in muscular disorders are limited. While in recent years there have been emerging indications regarding a relevant role of cellular stress in the pathophysiology of several muscular disorders, the underlying mechanisms are to a great extent incompletely understood. This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases. Potential mechanisms, as well as involved pathways are critically discussed, and respective disease models are addressed. Furthermore, relevant therapeutic approaches that aim to abrogate defects of cellular stress response in muscular disorders are outlined.
Highlights
The reaction of cells to internal or external changes of homeostasis by means of a concerted cellular stress response is a key aspect of cell survival and maintenance of cellular integrity [1]
One major activator of the unfolded protein response (UPR) is the aggregation of misfolded proteins in the Endoplasmic Reticulum (ER)-lumen, that is primarily sensed via three transmembrane proteins: RNA-dependent protein kinase-like ER eukaryotic translation initiation factor 2 alpha kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor-6 (ATF6)
A relevant upregulation of oxidative stress and NFκB-signalling has been identified in dysferlinopathy (LGMD2B/LGMDR2), a muscular dystrophy arising from mutation in the DYSF-gene
Summary
The reaction of cells to internal or external changes of homeostasis by means of a concerted cellular stress response is a key aspect of cell survival and maintenance of cellular integrity [1]. In context of neuromuscular disorders, a variety of recent studies suggest a relevant involvement of the cellular stress response in the pathogenesis of several neuromuscular diseases. The devastating motor neuron disorder amyotrophic lateral sclerosis (ALS) is by far the best studied disease model regarding a deregulated cellular stress machinery as a relevant pathogenetic mechanism This is partly due to the fact that the first gene identified to be involved in familial forms of ALS was the SOD1 gene [5]. The impact of the cellular stress response on homeostasis of the central and peripheral nervous system has been extensively studied, comparably little attention has been paid to the muscle as primary effector This is intriguingly surprising, as the muscle appears to be an organ that is exposed to changes of cellular homeostasis. Based on findings applicable to all muscular disorders, disease-specific findings are described, and emerging clinical consequences are discussed
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