Collagen VI is required for the structural and functional integrity of the neuromuscular junction

Cescon, Matilde; Gregorio, Ilaria Di; Eiber, Nane; Borgia, Doriana; Fusto, Aurora; Sabatelli, Patrizia; Scorzeto, Michele; Megighian, Aram; Pegoraro, Elena; Hashemolhosseini, Said; Bonaldo, Paolo

doi:10.1007/s00401-018-1860-9

Cited by 46 publications

(38 citation statements)

References 72 publications

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“…The synaptic cleft of the NMJ comprises a thickened and specialized ECM, which promotes proper formation and maintenance of NMJ structure and transmission. Indeed, Col6a1-deficient mice display phenotypes consistent with NMJ destabilization 68 . Together, these findings indicate that mTORC1 influences sarcopenia through a complex network of muscle fiber-intrinsic and extrinsic signaling events hinging on the NMJ.…”

Section: Discussionmentioning

confidence: 99%

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

et al. 2020

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With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

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Section: Discussionmentioning

confidence: 99%

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

et al. 2020

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“…COL6A1 encodes the alpha 1 subunit of collagen VI (ColVI) 28. ColVI is required for the structural and functional integrity of the neuromuscular junction 29. Mutations in glial cell line-derived neurotrophic factor ( GDNF ) have been suggested to act in concert with RET mutations to produce aganglionic megacolon (Hirschsprung’s disease), which is characterised by congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the GI tract 30.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Schafmayer¹,

Harrison²,

Buch³

et al. 2019

Gut

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ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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“…Regarding the vulnerability of NMJs to the loss of SH3TC2, increases of five different collagens suggest the activation of molecular mechanisms to prevent the complete breakdown of the NMJ. These proteins have been linked to structural and functional integrity as well as regeneration of the NMJ [47,48]. Moreover, collagens promote acetylcholine receptor clustering [49] and transcripts encoding for the gamma-subunit of the AChR were increased in gastrocnemius muscle of diseased animals (see above).…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

Cipriani

Phan

Médard

et al. 2018

IJMS

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The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the SH3TC2 gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the Sh3tc2 gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.

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Collagen VI is required for the structural and functional integrity of the neuromuscular junction

Cited by 46 publications

References 72 publications

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

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