Increased skeletal muscle expression of the endoplasmic reticulum chaperone GRP78 in patients with myasthenia gravis

Iwasa, Kazuo; Nambu, Yoshinori; Motozaki, Yuko; Furukawa, Yutaka; Yoshikawa, Hiroaki; Yamada, Masahito

doi:10.1016/j.jneuroim.2014.05.006

Cited by 17 publications

(13 citation statements)

References 24 publications

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“…Indeed, there are reports suggesting increased ER stress in muscle diseases such as myositis, which involves chronic inflammation, swelling, and weakness of skeletal muscle (35,36). Increased expression of ER stress markers has also been observed in the myopathy associated with myasthenia gravis (57,62).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

et al. 2016

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Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

et al. 2016

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“…It has been proposed that damage to acetylcholine receptor can induce ER stress in skeletal muscle. Indeed, elevated levels of GRP74 have been reported in muscle biopsies from patients with MG [151]. Moreover, higher binding of autoantibodies to ER chaperone GRP94 has been found to be associated with a subset of MG patients [152].…”

Section: Myasthenia Gravis (Mg)mentioning

confidence: 99%

ER stress in skeletal muscle remodeling and myopathies

2017

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Skeletal muscle is a highly plastic tissue in the human body that undergoes extensive adaptation in response to environmental cues, such as physical activity, metabolic perturbation, and disease conditions. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many mammalian cell types, including skeletal muscle. However, overload of misfolded or unfolded proteins in the ER lumen cause stress, which results in the activation of a signaling network called the unfolded protein response (UPR). The UPR is initiated by three ER transmembrane sensors: protein kinase R‐like endoplasmic reticulum kinase, inositol‐requiring protein 1α, and activating transcription factor 6. The UPR restores ER homeostasis through modulating the rate of protein synthesis and augmenting the gene expression of many ER chaperones and regulatory proteins. However, chronic heightened ER stress can also lead to many pathological consequences including cell death. Accumulating evidence suggests that ER stress‐induced UPR pathways play pivotal roles in the regulation of skeletal muscle mass and metabolic function in multiple conditions. They have also been found to be activated in skeletal muscle under catabolic states, degenerative muscle disorders, and various types of myopathies. In this article, we have discussed the recent advancements toward understanding the role and mechanisms through which ER stress and individual arms of the UPR regulate skeletal muscle physiology and pathology.

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“…This muscle-specific membrane protein localized to the sarcolemma and T-tubule system is usually needed for muscle repair and skeletal muscle development (83). Also, the glucose-regulated protein 78 (GRP78) mRNA that is activated by ER stress is increased, suggesting that muscle weakness in MG might be caused by both NMJ disruption and ER stress (84). Another intriguing observation relates to the bone mineral density at skeletal sites, which is significantly decreased in the femur of EAMG mice compared to control animals, in parallel with the severity of the disease (85).…”

Section: Molecular Changes and Mechanisms Of Compensationmentioning

confidence: 99%

The Muscle Is Not a Passive Target in Myasthenia Gravis

et al. 2019

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Myasthenia gravis (MG) is a rare autoimmune disease mediated by pathogenic antibodies (Ab) directed against components of the neuromuscular junction (NMJ), mainly the acetylcholine receptor (AChR). The etiological mechanisms are not totally elucidated, but they include a combination of genetic predisposition, triggering event(s), and hormonal components. MG disease is associated with defective immune regulation, chronic cell activation, inflammation, and the thymus is frequently abnormal. MG is characterized by muscle fatigability that is very invalidating and can be life-threatening when respiratory muscles are affected. MG is not cured, and symptomatic treatments with acetylcholinesterase inhibitors and immunosuppressors are lifelong medications associated with severe side effects (especially glucocorticoids). While the muscle is the ultimate target of the autoimmune attack, its place and role are not thoroughly described, and this mini-review will focus on the cascade of pathophysiologic mechanisms taking place at the NMJ and its consequences on the muscle biology, function, and regeneration in myasthenic patients, at the histological, cellular, and molecular levels. The fine structure of the synaptic cleft is damaged by the Ab binding that is coupled to focal complement-dependent lysis in the case of MG with anti-AChR antibodies. Cellular and molecular reactions taking place in the muscle involve several cell types as well as soluble factors. Finally, the regenerative capacities of the MG muscle tissue may be altered. Altogether, the studies reported in this review demonstrate that the muscle is not a passive target in MG, but interacts dynamically with its environment in several ways, activating mechanisms of compensation that limit the pathogenic mechanisms of the autoantibodies.

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Increased skeletal muscle expression of the endoplasmic reticulum chaperone GRP78 in patients with myasthenia gravis

Cited by 17 publications

References 24 publications

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

ER stress in skeletal muscle remodeling and myopathies

The Muscle Is Not a Passive Target in Myasthenia Gravis

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