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Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

ABSTRACT: The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = -0.56 and -0.59; both P < .001) whereas for fat fraction values are τ = -0.50 and -0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.

SUBMITTER: Otto LAM

PROVIDER: S-EPMC7507182 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

Otto Louise A M LAM van der Pol W-Ludo WL Schlaffke Lara L Wijngaarde Camiel A CA Stam Marloes M Wadman Renske I RI Cuppen Inge I van Eijk Ruben P A RPA Asselman Fay-Lynn FL Bartels Bart B van der Woude Danny D Hendrikse Jeroen J Froeling Martijn M

NMR in biomedicine 20200718 10

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor ...[more]

PMID: 32681555

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Project description:BackgroundSpinal muscular atrophy (SMA) is a health- and life-limiting neuromuscular disorder. Although varying degrees of mitochondrial abnormalities have been documented in SMA skeletal muscle, the influence of disease progression on pathways that govern organelle turnover and dynamics are poorly understood. Thus, the purpose of this study was to investigate skeletal muscle mitochondria during SMA disease progression and determine the effects of therapeutic modalities on organelle biology.MethodsSmn2B/+ and Smn2B/- severe SMA-like mice were used to investigate mitochondrial turnover and dynamics signalling. Muscles were analysed at postnatal day 9 (P9), P13 or P21 to address pre-symptomatic, early symptomatic and late symptomatic periods of the disorder. Additionally, we utilized an acute dose of exercise and urolithin A (UA) to stimulate organelle remodelling in skeletal muscle of SMA mice in vivo and in SMA patient-derived myotubes in vitro, respectively.ResultsSmn2B/+ and Smn2B/- mice demonstrated similar levels of muscle mitochondrial oxidative phosphorylation (OxPhos) proteins throughout disease progression. In contrast, at P21 the mRNA levels of upstream factors important for the transcription of mitochondrial genes encoded by the nuclear and mitochondrial DNA, including nuclear respiratory factor 2, sirtuin 1, mitochondrial transcription factor A and tumour protein 53, were upregulated (+31%-195%, p < 0.05) in Smn2B/- mice relative to Smn2B/+. Early and late symptomatic skeletal muscle from SMA-like mice showed greater autophagosome formation as denoted by more phosphorylated autophagy related 16-like 1 (p-ATG16L1Ser278) puncta (+60%-80%, p < 0.05), along with a build-up of molecules indicative of damaged mitochondria such as BCL2 interacting protein 3, Parkin and PTEN-induced kinase 1 (+100%-195%, p < 0.05). Furthermore, we observed a fragmented mitochondrial phenotype at P21 that was concomitant with abnormal splicing of Optic atrophy 1 transcripts (-53%, p < 0.05). A single dose of exercise augmented the expression of citrate synthase (+43%, p < 0.05) and corrected the over-assembly of autophagosomes (-64%, p < 0.05). In patient muscle cells, UA treatment stimulated autophagic flux, increased the expression of OxPhos proteins (+15%-47%, p < 0.05) and improved maximal oxygen consumption (+84%, p < 0.05).ConclusionsAbnormal skeletal muscle mitochondrial turnover and dynamics are associated with disease progression in Smn2B/- mice despite compensatory elevations in upstream factors important for organelle synthesis and recycling. Exercise and UA enhance mitochondrial health in skeletal muscle, which indicates that lifestyle-based and pharmacological interventions may be effective countermeasures targeting the organelle for therapeutic remodelling in SMA.

Project description:BackgroundSpinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle.MethodsWe thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-; SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations.ResultsHere, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-, and Fn14-/- mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models.ConclusionsOur study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Project description:BackgroundSpinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil.MethodsFasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at P < 0.05. For the remaining analyses, the Student's two-tail t test for paired variables and one-way analysis of variance (ANOVA) were used to test for differences between samples and data were considered significantly different at P < 0.05.ResultsFasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific.ConclusionsOur work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA and for other degenerative diseases characterized by muscular atrophy and postsynaptic immaturity.

Project description:Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA. Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally. Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content. Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

Dataset Information

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

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Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

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