Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily; Yazdani, Armin; Repentigny, Yves De; Kothary, Rashmi

doi:10.1038/srep28846

Cited by 28 publications

(45 citation statements)

References 58 publications

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“…Normalizing proteolytic pathways, such as autophagy and the ubiquitin–proteasome system (UPS), has been demonstrated to mitigate the SMA phenotype (Deguise et al . ). Since a single bout of exercise initiates the autophagy programme in the healthy condition (Vainshtein et al .…”

Section: Resultsmentioning

confidence: 97%

“…F ), similar to previous reports (Deguise et al . ). Acute exercise and recovery initiated a correction in the content of these critical UPS genes towards that of healthy Smn 2B/+ SED mice (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Dysregulated autophagy and UPS have been previously reported in these animals (Deguise et al . ), and pharmacological or genetic correction of these proteolytic pathways provides favourable outcomes in SMA‐like mice (Deguise et al . ; Rodriguez‐Muela et al .…”

Section: Discussionmentioning

confidence: 99%

“…), and pharmacological or genetic correction of these proteolytic pathways provides favourable outcomes in SMA‐like mice (Deguise et al . ; Rodriguez‐Muela et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, cellular SMN levels are regulated by protein degradation processes, such as the ubiquitin-proteasome and autophagy systems, which serve to dismantle dysfunctional molecules (Han et al 2012;Kwon et al 2013;Rodriguez-Muela et al 2018). These transcriptional and post-translational mechanisms of SMN expression are dysregulated in SMA, the correction of which may serve as potential therapeutic targets to mitigate the SMA pathology (Biondi et al 2008(Biondi et al , 2015Deguise et al 2016;Rodriguez-Muela et al 2018). While elevating SMN expression in central tissues, in particular the spinal cord and brain, improves health-and lifespan of SMA-like mice, the optimal mitigation of the pathology additionally requires augmented SMN levels in peripheral tissues (Hua et al 2011(Hua et al , 2015.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mikhail

Ljubicic

2019

The Journal of Physiology

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Key points Spinal muscular atrophy (SMA) is a health‐ and life‐limiting neuromuscular disorder caused by a deficiency in survival motor neuron (SMN) protein. While historically considered a motor neuron disease, current understanding of SMA emphasizes its systemic nature, which requires addressing affected peripheral tissues such as skeletal muscle in particular. Chronic physical activity is beneficial for SMA patients, but the cellular and molecular mechanisms of exercise biology are largely undefined in SMA. After a single bout of exercise, canonical responses such as skeletal muscle AMP‐activated protein kinase (AMPK), p38 mitogen‐activated protein kinase (p38) and peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) activation were preserved in SMA‐like Smn2B/− animals. Furthermore, molecules involved in SMN transcription were also altered following physical activity. Collectively, these changes were coincident with an increase in full‐length SMN transcription and corrective SMN pre‐mRNA splicing. This study advances understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression in muscle. Abstract Chronic physical activity is safe and effective in spinal muscular atrophy (SMA) patients, but the underlying cellular events that drive physiological adaptations are undefined. We examined the effects of a single bout of exercise on molecular mechanisms associated with adaptive remodelling in the skeletal muscle of Smn2B/− SMA‐like mice. Skeletal muscles were collected from healthy Smn2B/+ mice and Smn2B/− littermates at pre‐ (postnatal day (P) 9), early‐ (P13) and late‐ (P21) symptomatic stages to characterize SMA disease progression. Muscles were also collected from Smn2B/− animals exercised to fatigue on a motorized treadmill. Intracellular signalling and gene expression were examined using western blotting, confocal immunofluorescence microscopy, real‐time quantitative PCR and endpoint PCR assays. Basal skeletal muscle AMP‐activated protein kinase (AMPK) and p38 mitogen‐activated protein kinase (p38) expression and activity were not affected by SMA‐like conditions. Canonical exercise responses such as AMPK, p38 and peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) activation were observed following a bout of exercise in Smn2B/− animals. Furthermore, molecules involved in survival motor neuron (SMN) transcription, including protein kinase B (AKT) and extracellular signal‐regulated kinases (ERK)/ETS‐like gene 1 (ELK1), were altered following physical activity. Acute exercise was also able to mitigate aberrant proteolytic signalling in the skeletal muscle of Smn2B/− mice. Collectively, these changes were coincident with an exercise‐evoked increase in full‐length SMN mRNA expression. This study advances our understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression alongside AKT and ERK/ELK1 signalling.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

“…), and pharmacological or genetic correction of these proteolytic pathways provides favourable outcomes in SMA‐like mice (Deguise et al . ; Rodriguez‐Muela et al . ).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mikhail

Ljubicic

2019

The Journal of Physiology

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Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Deguise

Baranello

Mastella

et al. 2019

Ann Clin Transl Neurol

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125

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Objective Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods We analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

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Survival motor neuron deficiency slows myoblast fusion through reduced myomaker and myomixer expression

McCormack

Villalón

Viollet

et al. 2021

J cachexia sarcopenia muscle

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Background Spinal muscular atrophy is an inherited neurodegenerative disease caused by insufficient levels of the survival motor neuron (SMN) protein. Recently approved treatments aimed at increasing SMN protein levels have dramatically improved patient survival and have altered the disease landscape. While restoring SMN levels slows motor neuron loss, many patients continue to have smaller muscles and do not achieve normal motor milestones. While timing of treatment is important, it remains unclear why SMN restoration is insufficient to fully restore muscle size and function. We and others have shown that SMN‐deficient muscle precursor cells fail to efficiently fuse into myotubes. However, the role of SMN in myoblast fusion is not known. Methods In this study, we show that SMN‐deficient myoblasts readily fuse with wild‐type myoblasts, demonstrating fusion competency. Conditioned media from wild type differentiating myoblasts do not rescue the fusion deficit of SMN‐deficient cells, suggesting that compromised fusion may primarily be a result of altered membrane dynamics at the cell surface. Transcriptome profiling of skeletal muscle from SMN‐deficient mice revealed altered expression of cell surface fusion molecules. Finally, using cell and mouse models, we investigate if myoblast fusion can be rescued in SMN‐deficient myoblast and improve the muscle pathology in SMA mice. Results We found reduced expression of the muscle fusion proteins myomaker (P = 0.0060) and myomixer (P = 0.0051) in the muscle of SMA mice. Suppressing SMN expression in C2C12 myoblast cells reduces expression of myomaker (35% reduction; P < 0.0001) and myomixer, also known as myomerger and minion, (30% reduction; P < 0.0001) and restoring SMN levels only partially restores myomaker and myomixer expression. Ectopic expression of myomixer improves myofibre number (55% increase; P = 0.0006) and motor function (35% decrease in righting time; P = 0.0089) in SMA model mice and enhances motor function (82% decrease in righting time; P < 0.0001) and extends survival (28% increase; P < 0.01) when administered in combination with an antisense oligonucleotide that increases SMN protein levels. Conclusions Here, we identified reduced expression of muscle fusion proteins as a key factor in the fusion deficits of SMN‐deficient myoblasts. This discovery provides a novel target to improve SMA muscle pathology and motor function, which in combination with SMN increasing therapy could enhance clinical outcomes for SMA patients.

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Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

Cited by 28 publications

References 58 publications

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Survival motor neuron deficiency slows myoblast fusion through reduced myomaker and myomixer expression

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