Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy

Wakeling, Erin; Joussemet, Béatrice; Costiou, P.; Fanuel, Dominique; Moullier, Philippe; Barkats, Martine; Fyfe, John C.

doi:10.1002/cne.23010

Cited by 3 publications

(2 citation statements)

References 55 publications

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“…Interestingly, recent findings in different SMA animal models have highlighted the contribution of intrinsic skeletal muscle defects, with disruption of the myogenic program associated with a decrease in myofiber size and an increase in immature myofibers [ 36 ]. A study in an SMA feline model provided convincing evidence that motor neuron degeneration begins distal to the cell body and proceeds retrogradely (« dying-back process ») [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Mendili¹,

Lenglet²,

Stojkovic³

et al. 2016

PLoS ONE

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PurposeThe mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness.Materials and MethodsEighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores.ResultsCSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores.ConclusionsSpinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients.

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Section: Discussionmentioning

confidence: 99%

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Mendili¹,

Lenglet²,

Stojkovic³

et al. 2016

PLoS ONE

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“…The function of Lix1 expression regulation in skeletal muscle cell differentiation remains elusive. It has been suggested that Lix1 plays a role in radial growth of motor axons observed in feline spinal muscular atrophy [ 123 ]. We identified inverse regulation of Csdc2 expression during differentiation and TNF-α treatment relative to control cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Alpha and Insulin-Like Growth Factor 1 Induced Modifications of the Gene Expression Kinetics of Differentiating Skeletal Muscle Cells

Meyer

Krebs

Thirion³

et al. 2015

PLoS ONE

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IntroductionTNF-α levels are increased during muscle wasting and chronic muscle degeneration and regeneration processes, which are characteristic for primary muscle disorders. Pathologically increased TNF-α levels have a negative effect on muscle cell differentiation efficiency, while IGF1 can have a positive effect; therefore, we intended to elucidate the impact of TNF-α and IGF1 on gene expression during the early stages of skeletal muscle cell differentiation.Methodology/Principal FindingsThis study presents gene expression data of the murine skeletal muscle cells PMI28 during myogenic differentiation or differentiation with TNF-α or IGF1 exposure at 0 h, 4 h, 12 h, 24 h, and 72 h after induction. Our study detected significant coregulation of gene sets involved in myoblast differentiation or in the response to TNF-α. Gene expression data revealed a time- and treatment-dependent regulation of signaling pathways, which are prominent in myogenic differentiation. We identified enrichment of pathways, which have not been specifically linked to myoblast differentiation such as doublecortin-like kinase pathway associations as well as enrichment of specific semaphorin isoforms. Moreover to the best of our knowledge, this is the first description of a specific inverse regulation of the following genes in myoblast differentiation and response to TNF-α: Aknad1, Cmbl, Sepp1, Ndst4, Tecrl, Unc13c, Spats2l, Lix1, Csdc2, Cpa1, Parm1, Serpinb2, Aspn, Fibin, Slc40a1, Nrk, and Mybpc1. We identified a gene subset (Nfkbia, Nfkb2, Mmp9, Mef2c, Gpx, and Pgam2), which is robustly regulated by TNF-α across independent myogenic differentiation studies.ConclusionsThis is the largest dataset revealing the impact of TNF-α or IGF1 treatment on gene expression kinetics of early in vitro skeletal myoblast differentiation. We identified novel mRNAs, which have not yet been associated with skeletal muscle differentiation or response to TNF-α. Results of this study may facilitate the understanding of transcriptomic networks underlying inhibited muscle differentiation in inflammatory diseases.

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scAAV9 Intracisternal Delivery Results in Efficient Gene Transfer to the Central Nervous System of a Feline Model of Motor Neuron Disease

et al. 2013

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On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1-deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course.

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Failure of lower motor neuron radial outgrowth precedes retrograde degeneration in a feline model of spinal muscular atrophy

Cited by 3 publications

References 55 publications

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Tumor Necrosis Factor Alpha and Insulin-Like Growth Factor 1 Induced Modifications of the Gene Expression Kinetics of Differentiating Skeletal Muscle Cells

scAAV9 Intracisternal Delivery Results in Efficient Gene Transfer to the Central Nervous System of a Feline Model of Motor Neuron Disease

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