Impaired myogenic development, differentiation and function in hESC-derived SMA myoblasts and myotubes

Hellbach, Nicole; Peterson, Suzanne; Haehnke, Daniel; Shankar, Aditi; LaBarge, Samuel; Pivaroff, Cullen; Saenger, Stefanie; Thomas, Carolin; McCarthy, Kathleen; Ebeling, Martin; Bennett, Monica H; Schmidt, Uli; Metzger, Friedrich

doi:10.1371/journal.pone.0205589

Cited by 17 publications

(13 citation statements)

References 51 publications

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“…Although the muscle defects in our model mice and the therapeutic implications of such damage are obvious, precisely how low SMN triggers pathology remains to be explored. Some have suggested disruptions in the process of myogenesis (29,57,60,61). Although this may be true in the most severe form of SMA, it appeared to not be the case in our mutants, particularly those expressing 2 SMN2 copies.…”

Section: Discussioncontrasting

confidence: 54%

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models

Kim¹,

Jha²,

Feng³

et al. 2020

Journal of Clinical Investigation

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ResultsMyoD-iCre effects robust, muscle-specific inactivation of the Smn F7 allele. To investigate the cell-autonomous effects of depleting SMN in skeletal muscle, we began by testing which of 2 muscle Cre drivers, MyoD-iCre and Myf5-Cre (31, 32), was better suited for our studies. Each drives expression in muscle progenitor cells as early as E8 (33-35), and has been used to selectively deplete or restore disease-related proteins in skeletal muscle (27,36). To determine the tissue specificity of the 2 Cre lines, we separately bred the transgenic mice to animals harboring an inducible Smn deletion allele (Smn F7 ) bearing loxP sites on either side of exon 7 (37, 38). We then used PCR to examine which of the tissues of the double transgenics exhibited evidence of Cre-mediated recombination. As expected, we detected the presence of the deleted (Δ7) allele in the proximal and distal muscles of each of the double transgenic MyoD-iCre Smn F7 and Myf5-Cre Smn F7 animals ( Figure 1A). However, and consonant with other reports (27,39), whereas recombination of the Smn F7 allele was restricted to the skeletal muscle of the MyoD-iCre Smn F7 mice, it was also detected in the CNS tissue of the Myf5-Cre Smn F7 animals; the latter finding precluded the Myf5-Cre line for this study. We nevertheless proceeded to quantify the relative efficiency with which each of the Cre drivers effected Smn F7 inactivation in skeletal muscle. To directly measure how robustly each of the drivers converted the Smn F7 allele to the deleted Smn Δ7 form, we used Q-PCR on genomic DNA from the skeletal muscle of P7 MyoD-iCre Smn F7/+ and Myf5-Cre Smn F7/+ animals, and estimated relative levels of residual Smn F7 allele in each set of mutants. DNA from the muscle tissue of the MyoD-iCre Smn F7/+ mice contained lower levels of the Smn F7 allele than DNA from the muscle of Myf5-Cre Smn F7/+ mice ( Figure 1B), suggesting that MyoD-iCre is more robust in inactivating the floxed allele.As a second, indirect means of determining recombination efficiency, we established crosses to generate MyoD-iCre Smn F7/and Myf5-Cre Smn F7/mutants. In such mutants, the SMN protein

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Section: Discussioncontrasting

confidence: 54%

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models

Kim¹,

Jha²,

Feng³

et al. 2020

Journal of Clinical Investigation

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“…Severe Smn −/− ;SMN2 mice have a significantly increased osteoclast formation and bone resorption rate compared to wild-type mice [ 70 ]. Alternatively, abnormalities in calcium pathways have been reported in SMA (muscle [ 71 , 72 ], astrocytes [ 29 , 73 , 74 ], motor neurons [ 75 , 76 , 77 ], kidney [ 32 ]) and abnormal calcium levels have been inconsistently identified in SMA patients [ 32 , 47 , 67 ]. The specific mechanism and details of these studies are outside the scope of this review.…”

Section: Feeding Difficulties and Nutritional Intake Issuesmentioning

confidence: 99%

Metabolic Dysfunction in Spinal Muscular Atrophy

Deguise

Chehadé

Kothary

2021

IJMS

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Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.

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“…While SMA motor neurons have been thoroughly investigated, the knowledge about SMA muscles and their role in SMA pathology still remains elusive. It has been reported that SMA muscle cells show intrinsic defects in myogenic differentiation and energy metabolism [8, 9, 28] and that the proteome of skeletal muscles of presymptomatic SMA mice is dysregulated prior neuronal degeneration [50]. However, whether or how defects in muscles influence motor neuron physiology, and whether this contributes to SMA pathology is utterly unknown.…”

Section: Introductionmentioning

confidence: 99%

Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

Rehorst

Thelen

Nolte

et al. 2019

acta neuropathol commun

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Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

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Impaired myogenic development, differentiation and function in hESC-derived SMA myoblasts and myotubes

Cited by 17 publications

References 51 publications

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models

Metabolic Dysfunction in Spinal Muscular Atrophy

Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

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