Megf10 deficiency impairs skeletal muscle stem cell migration and muscle regeneration

Li, Chengcheng; Vargas‐Franco, Dorianmarie; Saha, Madhurima; Davis, Rachel Meredith; Manko, Kelsey; Draper, Isabelle; Pacak, Christina A.; Kang, Peter B.

doi:10.1002/2211-5463.13031

Cited by 9 publications

(17 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Murine Multiple Epidermal Growth Factor 10 (Megf10) was originally discovered in the same molecular screen to identify novel satellite cell markers that found Pax7 [ 48 ], and is the homologue of human MEGF10. Encoding a transmembrane protein, MEGF10 is highly expressed in adult skeletal muscle, and is involved in satellite cell proliferation and migration [ 49 , 50 ]. Frameshift deletions leading to translation of non-functional truncated protein, or complete mRNA loss in MEGF10 [ [51] , [52] , [53] ] associate with a recessive congenital severe myopathy called Myopathy, Areflexia, Respiratory Distress, And Dysphagia, Early-Onset (EMARDD; OMIM: 614399 ).…”

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

“…How lack or loss-of-function of MEGF10 leads to satellite cell dysfunction in EMARDD/MEGF10-myopathy is not fully understood, but loss of Megf10 activity is likely to have a major impact on the early phases of muscle regeneration. Muscle and myofibres in the Megf10-null mouse appear indistinguishable from wild-type [ 50 ], but muscle regeneration is severely impacted when modelling chronic regeneration in dystrophy, providing a possible explanation for onset/phenotype variability observed in patients. Murine Megf10- null muscles display expanding areas of myofibre atrophy, size variation and fibrosis and variable numbers of PAX7-positive cells, resembling the progressive myopathic phenotype reported in patients.…”

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

“…Murine Megf10- null muscles display expanding areas of myofibre atrophy, size variation and fibrosis and variable numbers of PAX7-positive cells, resembling the progressive myopathic phenotype reported in patients. Megf10 is highly expressed in quiescent and activated murine satellite cells [ 49 ], and the number of activated/proliferating Pax7/Myod double positive satellite cells is reduced in Megf10 -null mice [ 50 ]. Dysfunctional MEGF10 could inhibit self-renewal, expansion and migration during regeneration [ 49 ], since siRNA knockdown of mouse Megf10 results in decreased satellite cell proliferation and precocious differentiation [ 49 , 53 ].…”

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

See 2 more Smart Citations

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

View full text Add to dashboard Cite

Muscular dystrophies and congenital myopathies arise from specific genetic mutations causing skeletal muscle weakness that reduces quality of life. Muscle health relies on resident muscle stem cells called satellite cells, which enable life-course muscle growth, maintenance, repair and regeneration. Such tuned plasticity gradually diminishes in muscle diseases, suggesting compromised satellite cell function. A central issue however, is whether the pathogenic mutation perturbs satellite cell function directly and/or indirectly via an increasingly hostile microenvironment as disease progresses. Here, we explore the effects on satellite cell function of pathogenic mutations in genes (myopathogenes) that associate with muscle disorders, to evaluate clinical and muscle pathological hallmarks that define dysfunctional satellite cells. We deploy transcriptomic analysis and comparison between muscular dystrophies and myopathies to determine the contribution of satellite cell dysfunction using literature, expression dynamics of myopathogenes and their response to the satellite cell regulator PAX7. Our multimodal approach extends current pathological classifications to define Satellite Cell-opathies: muscle disorders in which satellite cell dysfunction contributes to pathology. Primary Satellite Cell-opathies are conditions where mutations in a myopathogene directly affect satellite cell function, such as in Progressive Congenital Myopathy with Scoliosis (MYOSCO) and Carey-Fineman-Ziter Syndrome (CFZS). Primary satellite cell-opathies are generally characterised as being congenital with general hypotonia, and specific involvement of respiratory, trunk and facial muscles, although serum CK levels are usually within the normal range. Secondary Satellite Cell-opathies have mutations in myopathogenes that affect both satellite cells and muscle fibres. Such classification aids diagnosis and predicting probable disease course, as well as informing on treatment and therapeutic development.

show abstract

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

See 1 more Smart Citation

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…Satellite cells can adopt several different states, including quiescence, activation, proliferation, and differentiation ( Li et al, 2021 ). Initially, during the perinatal and postnatal periods, satellite cells are proliferative ( Bröhl et al, 2012 ).…”

Section: Satellite Cellsmentioning

confidence: 99%

“…It should be noted that there are several interactions between the Notch pathway and other components in satellite cells, which work together to govern satellite cell proliferation. Multiple EGF-like domains 10 (MEGF10) is a transmembrane receptor expressed in both developing muscle satellite cells and myoblasts, which has exhibited marked similarity to Notch ( Saha et al, 2017 ; Draper et al, 2019 ; Li et al, 2021 ). MEGF10 regulates myogenesis in conjunction with the Notch pathway, and MEGF10 deficiency displays several characteristics similar to Notch deficiency ( Draper et al, 2019 ; Li et al, 2021 ).…”

Section: Other Proteins Associated With the Notch Pathway: Megf10 And...mentioning

confidence: 99%

Implications of notch signaling in duchenne muscular dystrophy

Hartog

Asakura

2022

Front. Physiol.

View full text Add to dashboard Cite

This review focuses upon the implications of the Notch signaling pathway in muscular dystrophies, particularly Duchenne muscular dystrophy (DMD): a pervasive and catastrophic condition concerned with skeletal muscle degeneration. Prior work has defined the pathogenesis of DMD, and several therapeutic approaches have been undertaken in order to regenerate skeletal muscle tissue and ameliorate the phenotype. There is presently no cure for DMD, but a promising avenue for novel therapies is inducing muscle regeneration via satellite cells (muscle stem cells). One specific target using this approach is the Notch signaling pathway. The canonical Notch signaling pathway has been well-characterized and it ultimately governs cell fate decision, cell proliferation, and induction of differentiation. Additionally, inhibition of the Notch signaling pathway has been directly implicated in the deficits seen with muscular dystrophies. Here, we explore the connection between the Notch signaling pathway and DMD, as well as how Notch signaling may be targeted to improve the muscle degeneration seen in muscular dystrophies.

show abstract

The Notch signaling pathway in skeletal muscle health and disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

The Notch signaling pathway is a key regulator of skeletal muscle development and regeneration. Over the past decade, the discoveries of three new muscle disease genes have added a new dimension to the relationship between the Notch signaling pathway and skeletal muscle: MEGF10, POGLUT1, and JAG2. We review the clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases. The phenotypes associated with two of these genes, POGLUT1 and JAG2, clearly fall within the realm of muscular dystrophy, whereas the third, MEGF10, is associated with a congenital myopathy/muscular dystrophy overlap syndrome classically known as early-onset myopathy, areflexia, respiratory distress, and dysphagia. JAG2 is a canonical Notch ligand, POGLUT1 glycosylates the extracellular domain of Notch receptors, and MEGF10 interacts with the intracellular domain of NOTCH1. Additional genes and their encoded proteins relevant to muscle function and disease with links to the Notch signaling pathway include TRIM32, ATP2A1 (SERCA1), JAG1, PAX7, and NOTCH2NLC. There is enormous potential to identify convergent mechanisms of skeletal muscle disease and new therapeutic targets through further investigations of the Notch signaling pathway in the context of skeletal muscle development, maintenance, and disease.

show abstract

Megf10 deficiency impairs skeletal muscle stem cell migration and muscle regeneration

Abstract: Bi-allelic loss-of-function MEGF10 mutations lead to MEGF10 myopathy, also known as early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD). MEGF10 is expressed in

Cited by 9 publications

References 58 publications

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Implications of notch signaling in duchenne muscular dystrophy

The Notch signaling pathway in skeletal muscle health and disease

Contact Info

Product

Resources

About