On the possible role of muscle in the pathogenesis of spinal muscular atrophy

Guettier‐Sigrist, Séverine; Braun, Serge; Rogovitz, David; Courdier, Isabelle; Warter, J; Poindron, Philippe

doi:10.1046/j.1472-8206.2001.00006.x

Cited by 23 publications

(16 citation statements)

References 27 publications

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“…While it is now clear that motor neurons are an important cellular site of action of the SMN protein (24)(25)(26), there is also mounting evidence for a contributing effect of reduced muscle SMN to the SMA phenotype (39)(40)(41)(42). Consistent with this notion, we observed evidence of a primary muscle myopathy in aging SMN-depleted 2-copy SMN2;CreER;Smn F7/-mice ( Figure 3E).…”

Section: Figuresupporting

confidence: 77%

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

Kariya¹,

Obis²,

Garone³

et al. 2014

J. Clin. Invest.

128

104

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Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs.

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Section: Figuresupporting

confidence: 77%

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

Kariya¹,

Obis²,

Garone³

et al. 2014

J. Clin. Invest.

128

104

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“…19 Based on these observations, we hypothesized that myotubes from SMA patients could be innervated and contracted as normal myotubes, but were unable to produce SMN-dependent signal essential for motoneuron survival. 20 This muscular hypothesis was confirmed by the fact that the deletion of SMN exon 7, the most frequently mutated exon in SMA, led to severe muscular dystrophy, proving that skeletal muscle is a target of the SMN gene defect, and confirming our idea that muscle involvement contributes to the motor defect in human SMA disease. 21 More recently, a deletion of SMN exon 7 was directed either to both satellite cells (the muscle progenitor cells) and fused myotubes, or to fused myotubes only.…”

supporting

confidence: 58%

“…This finding confirms that the of myotubes of the SMA I patients are immature 43 and is consistent with a study showing that expression of myf-5, a member of the muscle-regulatory factor family, is abnormal in embryonic SMA myogenic cells. 20 Thus, myogenesis is not appropriately regulated in SMA, but the proteins involved in contraction, such as actin and myosin are normally expressed (Figure 2b). A synchronized rate of muscle maturation with that of the motor activity is critical for the development of the NMJ.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

Arnold¹,

Gueye²,

Guettier‐Sigrist³

et al. 2004

Laboratory Investigation

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motoneurons and skeletal muscle atrophy. In its most severe form, it leads to death before the age of 2 years. While primary degeneration of motor neurons is well established in this disease, and this results in neurogenic atrophy of skeletal muscle, we have previously reported evidence for a primary muscle defect. In this study, we used primary cultures of embryonic human skeletal muscle cells from patients with SMA and from controls to examine the effects of muscle fiber differentiation in the absence of a nerve component. Cultured SMA skeletal muscle cells are unable to fuse correctly to form multinuclear myotubes, the precursors of the myofibers. We also show that agrin-induced aggregates of nicotinic acetylcholine receptors, one of the earliest steps of neuromuscular junction formation, cannot be visualized by confocal microscopy on cells from SMA patients. In binding experiments, we demonstrate that this lack of clustering is due to defective expression of the nicotinic acetylcholine receptors in the myotubes of SMA patients whereas the affinity of a-bungarotoxin for its receptor remains unchanged regardless of muscle cell type (SMA or control). These observations suggest that muscle cells from SMA patients have intrinsic abnormalities that may affect proper formation of the neuromuscular junction. Keywords: spinal muscular atrophy; myotubes; neuromuscular junction; nicotinic acetylcholine receptors; aggregation; binding Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of spinal motor neurons leading to a muscle weakness and paralysis. SMA is traditionally classified into three types based on the age of onset and the severity of symptoms. 1 The SMA I or Werdnig-Hoffmann disease is the most severe form. Patients never attain the ability to sit, and their lifespan does not exceed infancy in most cases. SMA II is the intermediate form. Patients are unable to stand or walk unaided, and death usually occurs in adulthood. SMA III or Kugelberg-Welander disease presents a milder phenotype. Patients are able to stand and walk and present a near-normal life expectancy. The gene responsible for all three types of SMA was mapped to the region 5q11.2-13.3 by linkage analysis. [2][3][4][5] This gene, named SMN for 'survival of motor neurons', is mutated in 98% of the SMA patients, and the majority of mutations occur in exon 7. 6 It encodes a ubiquitously expressed SMN protein present in both the cytoplasm and the nucleus. In this last compartment, the SMN protein is concentrated in structures called gems (for 'gemini of coiled bodies') located in the close proximity of Cajal bodies (previously named coiled bodies). 7,8 The SMN protein participates in the formation of the SMN complex, which is associated with small nuclear ribonucleoproteins (snRNP) in the cytoplasm and plays a crucial role in the spliceosomal snRNP assembly. 9 In the nucleus, the SMN complex participates in the regener...

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“…Although no functional synapses appear in a simple muscle cell-motor neuron coculture, it seems that motor neurons can induce some muscle cell differentiation as soon as an axon has contacted its target. Finally, we have observed 15 that in nerve-muscle coculture, muscle satellite cells behave abnormally and expression of myf-5 (a transcription factor involved in the early steps of myogenesis) is impaired, which suggests an impairment of the maturation process.…”

Section: Discussionmentioning

confidence: 95%

Possible pathogenic role of muscle cell dysfunction in motor neuron death in spinal muscular atrophy

Guettier‐Sigrist¹,

Hugel²,

Coupin³

et al. 2002

Muscle and Nerve

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We have previously shown that myofibers formed by fusion of muscle satellite cells from spinal muscular atrophy (SMA) I or II undergo degeneration 1 to 3 weeks after innervation by rat embryonic spinal cord explants, whereas normal myofibers survive for several months. In the "muscle component" of the coculture, the only cells responsible for the degeneration are the SMA muscle satellite cells. Moreover, SMA muscle satellite cells do not fuse as rapidly as do normal muscle satellite cells. To determine whether death of muscle cells precedes that of motor neurons, we studied the origin and kinetics of release of apoptotic microparticles. In SMA cocultures, motor neuron apoptosis occurred before myofiber degeneration becomes visible, indicating that SMA myofibers were unable to sustain survival of motor neurons. In normal cocultures, motor neuron apoptosis occurred 4 days after innervation. However, it did not continue beyond 2 days. These results strengthen the hypothesis that SMA is due to a defect in neurotrophic muscle cell function.

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On the possible role of muscle in the pathogenesis of spinal muscular atrophy

Cited by 23 publications

References 27 publications

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients

Possible pathogenic role of muscle cell dysfunction in motor neuron death in spinal muscular atrophy

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