New roles for desmin in the maintenance of muscle homeostasis

Agnetti, Giulio; Herrmann, Harald; Cohen, Shenhav

doi:10.1111/febs.15864

Cited by 72 publications

(59 citation statements)

References 111 publications

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“…The muscle-specific type III intermediate filament (IF) desmin is essential for a proper muscular structure and function. Because desmin IF connects adjacent myofibrils with each other as well as to the sarcolemma, nucleus and mitochondria, they are important for the mechanical and structural integrity of myofibrils [ 113 ]. Importantly, it has been shown that the loss of desmin IF during starvation- or denervation-induced atrophy precedes and promotes myofibril destruction [ 114 ].…”

Section: Protein Turnover In Muscle Is Regulated By a Precisely Acting Protein Degradation Pathwaymentioning

confidence: 99%

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

2021

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The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.

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Section: Protein Turnover In Muscle Is Regulated By a Precisely Acting Protein Degradation Pathwaymentioning

confidence: 99%

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

2021

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“…Intermediate filaments. Desmin is one of the major cytoplasmic intermediate filaments in the skeletal muscle and maintains mechanical integrity during contraction [ 181 ]. Mutations in desmin cause desmin-related myopathy (OMIM#601419) and cardiomyopathy (OMIM#604765).…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

“…Mutations in desmin cause desmin-related myopathy (OMIM#601419) and cardiomyopathy (OMIM#604765). Desmin localizes to Z-disk, where it plays a key role in the integration and maintenance of the structure and function of striated muscle [ 181 ]. Specifically, desmin anchors several structures (mitochondria, nucleus, and Z-disk) to the sarcolemma cytoskeleton at the costamere and regulates peripheral nuclei positioning in myofibers [ 182 ].…”

Section: Common Pathomechanisms Of Cnmsmentioning

confidence: 99%

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Gómez-Oca

Cowling²,

Laporte

2021

IJMS

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Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

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“…Compromising effects of Dsg2 mutation on cell mechanics are most likely mediated through altered desmosomal cell-cell adhesion at the intercalated disc and changes in the three-dimensional organization of the desmosome-anchored desmin intermediate filament network. The latter forms a complex scaffold for organelles and myofibrils [ 73 , 74 , 75 ]. The recently observed considerably altered desmin organization in Dsg2 mutants during embryonic cardiogenesis with detrimental consequences on cardiac differentiation and function underscores the importance of an intact desmin network for cellular integrity [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy

Pitsch

Kant

Mytzka

et al. 2021

Cells

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Arrhythmogenic cardiomyopathy (AC) is a heritable, potentially lethal disease without a causal therapy. AC is characterized by focal cardiomyocyte death followed by inflammation and progressive formation of connective tissue. The pathomechanisms leading to structural disease onset and progression, however, are not fully elucidated. Recent studies revealed that dysregulation of autophagy and endoplasmic/sarcoplasmic reticulum (ER/SR) stress plays an important role in cardiac pathophysiology. We therefore examined the temporal and spatial expression patterns of autophagy and ER/SR stress indicators in murine AC models by qRT-PCR, immunohistochemistry, in situ hybridization and electron microscopy. Cardiomyocytes overexpressing the autophagy markers LC3 and SQSTM1/p62 and containing prominent autophagic vacuoles were detected next to regions of inflammation and fibrosis during onset and chronic disease progression. mRNAs of the ER stress markers Chop and sXbp1 were elevated in both ventricles at disease onset. During chronic disease progression Chop mRNA was upregulated in right ventricles. In addition, reduced Ryr2 mRNA expression together with often drastically enlarged ER/SR cisternae further indicated SR dysfunction during this disease phase. Our observations support the hypothesis that locally altered autophagy and enhanced ER/SR stress play a role in AC pathogenesis both at the onset and during chronic progression.

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New roles for desmin in the maintenance of muscle homeostasis

Cited by 72 publications

References 111 publications

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy

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