Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3

Wadman, Renske I.; Vrancken, Alexander F.J.E.; Berg, Leonard H van den; Pol, W. Ludo van der

doi:10.1212/wnl.0b013e3182749eca

Cited by 84 publications

(76 citation statements)

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“…Recent observations of immature protein composition of neuromuscular junctions in SMA models and patients support this notion. 55,56 Maturation of muscle fibers and activation of mitochondrial biogenesis are closely related. The reduced mitochondrial content makes SMA muscle unable to sustain muscle fiber maturation and contraction properly, contributing to patient weakness and hypotonia.…”

Section: Discussionmentioning

confidence: 99%

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

et al. 2015

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The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).OBJECTIVE To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTSWe studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015.EXPOSURES We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES Respiratory chain activity and mitochondrial content.RESULTS Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05). CONCLUSIONS AND RELEVANCEOur results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.

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Section: Discussionmentioning

confidence: 99%

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

et al. 2015

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“…NMJ dysfunction has been identified in SMA mouse models and patients . In individuals with SMA, fatigue on the 6MWT was associated with a decrement on low‐rate repetitive nerve stimulation, possibly due to developmental NMJ abnormalities or NMJ function alterations .…”

Section: Discussionmentioning

confidence: 99%

“…Fatigue measured during the 6MWT may represent underlying disease‐specific mechanisms, and improvements may represent treatment benefit. Neuromuscular junction (NMJ) development and maturation abnormalities, including immaturity, denervation, and neurofilament accumulation, as well as endocytosis and axonal transport abnormalities, have been identified in animal models and in individuals with SMA . Data suggesting a relationship between NMJ dysfunction and fatigability have been reported …”

Section: Introductionmentioning

confidence: 99%

Nusinersen improves walking distance and reduces fatigue in later‐onset spinal muscular atrophy

et al. 2019

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Introduction Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied. Methods Post hoc analyses were used to examine changes in 6‐minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open‐label CS2 study and were ambulatory during CS2 or the extension study, CS12. Results Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by −3.8% (−19.7%, 1.4%). Discussion These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later‐onset SMA.

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“…Van der Pol reviewed his published data, which demonstrated a decremental response of the CMAP with low frequency repetitive stimulation in a proportion of SMA patients, suggestive of a post-synaptic physiological defect [18]. This may be relevant to muscle fatigue, a common symptom in SMA.…”

Section: Article In Pressmentioning

confidence: 98%

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

Finkel

Bertini²,

Muntoni

et al. 2015

Neuromuscular Disorders

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Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3

Abstract: These data suggest dysfunction of the neuromuscular junction in patients with SMA types 2 and 3. Therefore, drugs that facilitate neuromuscular transmission are candidate drugs for evaluation in carefully designed, placebo-controlled, clinical trials.

Cited by 84 publications

References 39 publications

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

Nusinersen improves walking distance and reduces fatigue in later‐onset spinal muscular atrophy

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

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