A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

Deguise, Marc-Olivier; Pileggi, Chantal; Beauvais, Ariane; Tierney, Alexandra; Chehadé, Lucia; Repentigny, Yves De; Michaud, Jean; Llavero-Hurtado, Maica; Lamont, Douglas J.; Atrih, Abdelmadjid; Wishart, Thomas M.; Gillingwater, Thomas H.; Schneider, Bernard L.; Harper, Mary‐Ellen; Parson, Simon H.; Kothary, Rashmi

doi:10.1101/2020.04.29.051938

Cited by 3 publications

(5 citation statements)

References 70 publications

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“…Decreased CPT activity has been reported in muscles of severe type 1 SMA patients, compared with aged-matched infants [ 56 ]. Recently, reduced CPT1 activity was also found in an SMA (Smn 2B/− ) mice model [ 25 ]. Of note, an isoform of CPT1, called CPT1c, which mainly expresses in neurons, including motor neurons, shows biosynthetic activity in neuron-specific acyl-CoA.…”

Section: Lipid Metabolic Abnormalities In Smamentioning

confidence: 99%

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Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Chen

et al. 2020

Nutrients

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Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

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Section: Lipid Metabolic Abnormalities In Smamentioning

confidence: 99%

“… Overview of non-neuromuscular systemic pathology in spinal muscular atrophy (SMA). A summary of multi-organ involvement has been reported in SMA animal models and/or patients [ 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. …”

Section: Figurementioning

confidence: 99%

Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Chen

et al. 2020

Nutrients

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“…Therefore, the increased serum IGFBP‐5 levels might be unfavorable to SMA patients who already had reduced total IGF‐I levels. The liver‐intrinsic defects that were identified in SMA were considered as another factor that might be causing serum IGF‐I reduction 39–43 . Although there was no indication of liver dysfunction in SMA patients in the current study, it needs to be further evaluated in larger cohorts.…”

Section: Discussionmentioning

confidence: 77%

“…The liverintrinsic defects that were identified in SMA were considered as another factor that might be causing serum IGF-I reduction. [39][40][41][42][43] Although there was no indication of liver dysfunction in SMA patients in the current study, it needs to be further evaluated in larger cohorts.…”

Section: Discussionmentioning

confidence: 83%

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

et al. 2022

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Introduction/Aims: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Methods: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls.Results: A significant decrease in IGF-I levels (mean ± SD: À1.39 ± 1.46 vs. 0.017 ± 0.83, p = .02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p = .03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway.Discussion: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

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“…SMN functions in spliceosome assembly and ribonucleoprotein biogenesis in all cells [2] and is potentially involved in autophagy, endocytosis, mRNA trafficking and local translation, cytoskeletal dynamics, mitochondria and bioenergetic pathways, and ubiquitin-proteasome system [5], leading to additional systemic effects mainly observed in humans in the most severe cases [6,7]. There is accumulating evidence from animal models of SMA for the involvement of muscle [8], NMJs [9], liver [10], heart [11], and vascular endothelium [12] in the pathology of SMA, but clear evidence of clinical involvement of these organs in humans is limited to the most severe SMA cases.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities

Servais

Baranello

Scoto

et al. 2021

Expert Opinion on Investigational Drugs

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Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein, while a second gene, SMN2, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset. Areas covered: Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent. Expert opinion: Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.

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A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

Cited by 3 publications

References 70 publications

Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

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

Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities

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