Alterations in insulin‐like growth factor system in spinal muscular atrophy

Kaymaz, Ayşe Yeşbek; Bal, Sevgi Köstel; Bora, Gamze; Talim, Beril; Özön, Alev; Alikaşifoğlu, Ayfer; Topaloǧlu, Haluk; Erdem‐Yurter, Hayat

doi:10.1002/mus.27715

Cited by 7 publications

(6 citation statements)

References 56 publications

(103 reference statements)

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“…A vitro experiment verified that the decreased level of Igfbp5 protein restrained the proliferation and differentiation of bovine skeletal muscle satellite cells ( 91 ). Conversely, in a recent study, increased expression of Igfbp5 was detected in skeletal muscle biopsies of spinal muscular atrophy (SMA) patients and non-SMA neuromuscular diseases ( 92 ). In our study, the decreased expression of Igfbp5 in qPCR validation was also inconsistent with the transcriptome sequencing, which was probably attributed to the difference in muscle tissues or individuals.…”

Section: Discussionmentioning

confidence: 89%

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

et al. 2023

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Sarcopenia is a senile disease with high morbidity, serious complications and limited clinical treatments. Menopause increases the risk of sarcopenia in females, while the exact pathogenesis remains unclear. To systematically investigate the development of hormone-related sarcopenia, we established a model of sarcopenia by ovariectomy and recorded successive characteristic changes. Furthermore, we performed the transcriptome RNA sequencing and bioinformatics analysis on this model to explore the underlying mechanism. In our study, we identified an integrated model combining obesity, osteoporosis and sarcopenia. Functional enrichment analyses showed that most of the significantly enriched pathways were down-regulated and closely correlated with endocrine and metabolism, muscle dysfunction, cognitive impairment and multiple important signaling pathways. We finally selected eight candidate genes to verify their expression levels. These findings confirmed the importance of estrogen in the maintenance of skeletal muscle function and homeostasis, and provided potential targets for further study on hormone-related sarcopenia.

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Section: Discussionmentioning

confidence: 89%

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

et al. 2023

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“…Conversely, selective depletion of SMN in motor neurons alone results in a milder SMA phenotype as compared with systemic depletion ( 67 ), while selective restoration of SMN in neural tissue leads to only partial rescue of the SMA phenotype ( 68 ). It is possible that effects on SMA neuromuscular function could be mediated through peripheral organ secretion of neurotrophic factors such as IGF-1, which, together with its binding protein IGFALS has reduced expression in patients and mouse models of SMA ( 64 , 69 ). Further studies to investigate whether non–motor neuron, cell-autonomous SMN rescue in liver and other peripheral organs has a role in motor neuron function and overall survival in SMA patients would increase our understanding of the pathology and natural history of SMA, and clinical implications of extraneuronal and treatment-modified phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Leow,

Ng,

Wang

et al. 2024

Journal of Clinical Investigation

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Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extraneuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyteintrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyteintrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.

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“…Immunoassays from previous research revealed that SMA patients have significantly lower levels of insulin‐like growth factor‐1 (IGF‐1) in their serum 35 . As IGF‐1 is necessary for the general growth of individuals, 36 restoration of the IGF‐1 level would be important for SMA patients whose height and weight have been reported to be lower than those of healthy individuals 37 .…”

Section: Discussionmentioning

confidence: 99%

Improved therapeutic approach for spinal muscular atrophy via ubiquitination‐resistant survival motor neuron variant

Rhee,

Kang,

et al. 2024

J cachexia sarcopenia muscle

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BackgroundZolgensma is a gene‐replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre‐symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination‐resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild‐type SMN (SMNWT).MethodsA severe SMA mouse model, SMA type 1.5 (Smn−/−; SMN2+/+; SMN∆7+/−) mice, was used to compare the differences in therapeutic efficacy between AAV9‐SMNWT and AAV9‐SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle.ResultsAAV9‐SMNK186R‐treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9‐SMNWT‐treated mice. Lifespan increased by more than 10‐fold in AAV9‐SMNK186R‐treated mice (144.8 ± 26.11 days) as compared with AAV9‐SMNWT‐treated mice (26.8 ± 1.41 days). AAV9‐SMNK186R‐treated mice showed an ascending weight pattern, unlike AAV9‐SMNWT‐treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9‐SMNK186R‐treated mice turned their bodies in an upward direction successfully, unlike AAV9‐SMNWT‐treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9‐SMNK186R‐treated mice, unlike AAV9‐SMNWT‐treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5‐fold) and the size of myofibers (2.1‐fold) were significantly increased in AAV9‐SMNK186R‐treated mice compared with AAV9‐SMNWT‐treated mice without prominent neurotoxicity. AAV9‐SMNK186R had fewer liver defects compared with AAV9‐SMNWT, as judged by increased proliferation of hepatocytes (P < 0.0001) and insulin‐like growth factor‐1 production (P < 0.0001). Especially, low‐dose AAV9‐SMNK186R (nine‐fold) also reduced clasping time compared with SMNWT.ConclusionsSMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low‐dose treatment of SMA patients with AAV9‐SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.

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Alterations in insulin‐like growth factor system in spinal muscular atrophy

Cited by 7 publications

References 56 publications

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy

Improved therapeutic approach for spinal muscular atrophy via ubiquitination‐resistant survival motor neuron variant

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