Exercise Training Reverses Skeletal Muscle Atrophy in an Experimental Model of VCP Disease

Nalbandian, Angèle; Nguyen, Christopher; Katheria, Veeral; Llewellyn, Katrina J.; Badadani, Mallikarjun; Caiozzo, Vincent J.; Kimonis, Virginia

doi:10.1371/journal.pone.0076187

Cited by 26 publications

(22 citation statements)

References 45 publications

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“…Thus, the remainder of the study was conducted using our unique VCP R155H/+ heterozygote experimental mouse model, which features clinical characteristics that closely mimics human VCP-associated myopathy [27, 34, 35]. Altogether, these results from immunocytochemistry, Western blotting and flow cytometry corroborate to confirm activation of the NLRP3 inflammasome in human VCP myoblasts and that this activation can be significantly downregulated following in vitro treatment with the MCC950 Inhibitor.…”

Section: Resultsmentioning

confidence: 57%

“…Untreated age- and sex-matched VCP R155H/+ heterozygotes mice were used as controls. Muscle strength was also compared between MCC950 treated and untreated mice using muscle grips as previously described [27]. Grip strength in MCC950-treated 12-month old VCP R155H/+ mice was significantly higher than that in untreated mice ( p<0.045 ) (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Expression levels of proteins were analyzed by Western blotting using NLRP3 (1:3,000 dilution), TDP-43 (1:3,000 dilution), IL-1β (1:3,000 dilution), IL-18 (1:3,000 dilution), Caspase 1 (1:3,000 dilution; cleaved p10 and p20) inflammatory mediators and correlate with loss of muscle function. These antibodies were previously validated in our most recent publications [21, 26, 27]. All antibodies were purchased from Abcam (Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

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Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

et al. 2016

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Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with Valosin Containing Protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones and brain. In this report, we demonstrate: (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, Caspase 1, IL-1β and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β (+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1β (+) macrophage infiltrates in the muscle and significantly ameliorated muscle strength. Together, these results suggest: (i) NLRP3 inflammasome and local IL-1β (+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy; and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

et al. 2016

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“…186 In mice with experimentally induced myopathy and increased autophagy proteins (LC3-II and SQSTM1/p62), 6 wk of exercise training prevents these changes leading to an improvement in muscle function and a decrease in atrophy. 187 There is growing evidence suggesting that exercise, through the activation of previously suppressed autophagy, may provide beneficial effects. In dystrophic mice, voluntary exercise improves markers of oxidative capacity and autophagy levels, suggesting that exercise-induced autophagy levels account for exercise benefits.…”

Section: Exercise Modulates Autophagy In Animalsmentioning

confidence: 99%

Heat shock response and autophagy—cooperation and control

2015

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Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate-activated protein kinase; ATG, autophagy-related; BECN1, Beclin 1, autophagy related; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSPA8/ HSC70, heat shock 70kDa protein 8; IL, interleukin; LC3, MAP1LC3, microtubule-associated protein 1 light chain 3; MTMR14/ hJumpy, myotubularin related protein 14; MTOR, mechanistic target of rapamycin; NR1D1/Rev-Erb-a, nuclear receptor subfamily 1, group D, member 1; PBMC, peripheral blood mononuclear cell; PPARGC1A/PGC-1a, peroxisome proliferator-activated receptor, gamma, coactivator 1 a; RHEB, Ras homolog enriched in brain; SOD, superoxide dismutase; SQSTM1/p62, sequestosome 1; TPR, translocated promoter region, nuclear basket protein; TSC, tuberous sclerosis complex; ULK1, unc-51 like autophagy activating kinase 1.Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.

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“…For example, it has been shown that the expression of the histone deacetylase-6 (HDAC6), a ubiquitin-binding deacetylase participating to autophagosomelysosome fusion and substrate degradation, is able to improves aggresome formation and protects IBMPFD mutant cells from polyglutamine-induced cell death [49,50]. In addition, very recently a very detailed experimental study has shown that a 6-week lowintensity uphill treadmill exercise regimen can improve the wholebody strength, and mitochondrial oxidative capacity of the quadriceps muscles of a IBMPFD mouse model [51]. However, further studies are required to clarify whether this experimental evidence can be beneficial in designing a future avenue of treatment of this disorder.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Hereditary inclusion-body myopathies

Broccolini¹,

Mirabella²

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The term hereditary inclusion-body myopathies (HIBMs) defines a group of rare muscle disorders with autosomal recessive or dominant inheritance and presence of muscle fibers with rimmed vacuoles and collection of cytoplasmic or nuclear 15-21 nm diameter tubulofilaments as revealed by muscle biopsy. The most common form of HIBM is due to mutations of the GNE gene that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. This results in abnormal sialylation of glycoproteins that possibly leads to muscle fiber degeneration. Mutations of the valosin containing protein are instead responsible for hereditary inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), with these three phenotypic features having a variable penetrance. IBMPFD probably represents a disorder of abnormal cellular trafficking of proteins and maturation of the autophagosome. HIBM with congenital joint contractures and external ophthalmoplegia is due to mutations of the Myosin Heavy Chain IIa gene that exerts a pathogenic effect through interference with filament assembly or functional defects in ATPase activity. This review illustrates the clinical and pathologic characteristics of HIBMs and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

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Exercise Training Reverses Skeletal Muscle Atrophy in an Experimental Model of VCP Disease

Cited by 26 publications

References 45 publications

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Heat shock response and autophagy—cooperation and control

Hereditary inclusion-body myopathies

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