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

Abstract

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.

Fine-Tuning of Piezo1 Expression and Activity Ensures Efficient Myoblast Fusion during Skeletal Myogenesis

“…Piezo1 s importance in skeletal muscle maintenance and function will undoubtedly grow as new research aims to explore the mechanisms and signalling pathways this remarkable mechanosensor employs. Moreover, given Piezo1's pivotal role in myogenic progression and its expression in satellite cells, it is likely that altered Piezo1 activity may associate with pathogenesis of satellite cell-opathies [37].…”

Antagonism Between DUX4 and DUX4c Highlights a Pathomechanism Operating Through β-Catenin in Facioscapulohumeral Muscular Dystrophy

“…Thus, DUX4-induced alteration in WNT/β-CATENIN signalling would also contribute to inefficient muscle regeneration in FSHD ( Banerji et al, 2020b ). We recently defined FSHD as a secondary Satellite Cell-opathy ( Ganassi et al, 2022 ; Ganassi and Zammit, 2022 ), given that DUX4 affects both satellite cell/myoblast and muscle fibre function, and suppression of PAX7 target genes ( Banerji et al, 2017 ; Banerji and Zammit, 2021 ). Here, we found that DUX4-mediated activation of β-CATENIN signalling does not promote a coordinated ‘myogenic differentiation’ transcriptome.…”

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

“…Defects in cell-cell fusion are involved in infertility ( 34 ), preeclampsia ( 35 ), osteoporosis ( 36 ), cancer ( 37 ), and infection ( 10 , 38 ). In skeletal muscle, alterations in myoblast fusion have been reported to contribute to the pathology of human neuromuscular diseases ( 39 , 40 ) such as Duchenne muscular dystrophy ( 41 , 42 ), limb-girdle muscular dystrophy ( 43 ), and Emery-Dreifuss muscular dystrophy ( 44 ). The discovery of pathogenic variants in MYMK and MYMX highlights a new form of fusogenic myopathy.…”