Developmental myosins: expression patterns and functional significance

Schiaffino, Stefano; Rossi, Alberto; Smerdu, Vika; Leinwand, Leslie A.; Reggiani, Carlo

doi:10.1186/s13395-015-0046-6

Cited by 411 publications

(421 citation statements)

References 111 publications

(145 reference statements)

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“…The developmental marker eMHC is expressed in newly forming myofibers (44,45). Consistent with this, we observed that it was strongly expressed in regenerating control and Pak1 Ϫ/Ϫ muscle at D5PI, with a slight reduction in Pak2 cKO mice (Fig.…”

Section: Resultssupporting

confidence: 86%

Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro

Joseph

Lü

Radu

et al. 2017

Molecular and Cellular Biology

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Skeletal myogenesis is regulated by signal transduction, but the factors and mechanisms involved are not well understood. The group I Paks Pak1 and Pak2 are related protein kinases and direct effectors of Cdc42 and Rac1. Group I Paks are ubiquitously expressed and specifically required for myoblast fusion in Drosophila. We report that both Pak1 and Pak2 are activated during mammalian myoblast differentiation. One pathway of activation is initiated by N-cadherin ligation and involves the cadherin coreceptor Cdo with its downstream effector, Cdc42. Individual genetic deletion of Pak1 and Pak2 in mice has no overt effect on skeletal muscle development or regeneration. However, combined muscle-specific deletion of Pak1 and Pak2 results in reduced muscle mass and a higher proportion of myofibers with a smaller cross-sectional area. This phenotype is exacerbated after repair to acute injury. Furthermore, primary myoblasts lacking Pak1 and Pak2 display delayed expression of myogenic differentiation markers and myotube formation. These results identify Pak1 and Pak2 as redundant regulators of myoblast differentiation in vitro and in vivo and as components of the promyogenic Ncad/Cdo/Cdc42 signaling pathway.KEYWORDS Pak, cell adhesion, cell differentiation, myogenesis, regeneration, signal transduction C ell differentiation is a complex process whereby precursor cells take on tissuespecific structure and function. Lineage-restricted transcription factors lie at the heart of cell differentiation, but the process is often initiated and fortified by ubiquitous signaling pathways that function in many biological contexts. Skeletal myogenesis serves as a paradigm for cell differentiation. Differentiation of skeletal myoblasts is a coordinated process involving adoption of a cell-type-specific transcriptional program and morphological changes, including fusion into multinucleated myofibers (1, 2). MyoD family proteins (MyoD, Myf5, myogenin, and MRF4) are muscle-specific transcription factors that act in concert with other, more broadly expressed transcription factors to establish the muscle phenotype (1, 3). The activities of these factors are regulated posttranslationally by non-muscle-specific signal transduction pathways. One such pathway is the p38␣/␤ mitogen-activated protein kinase (MAPK; here simply p38) pathway (4). p38 is activated during myogenic differentiation in vitro, and its inhibition results in impaired differentiation (5-7). Furthermore, mice lacking p38␣ exhibit delayed myofiber growth and maturation (8).The signals that initiate p38 activity during myoblast differentiation are poorly understood. One mechanism is via activation of a signaling complex nucleated at sites of cadherin-based cell-cell adhesion (9, 10). The transmembrane IgSF coreceptor Cdo (also called Cdon) is bound in cis to N-cadherin (Ncad) in myoblasts. During myoblast differentiation, or acutely upon Ncad ligation, the Cdo intracellular region associates directly with (i) Bnip-2, a scaffold protein for Cdc42, and (ii) JLP, a scaffo...

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Section: Resultssupporting

confidence: 86%

Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro

Joseph

Lü

Radu

et al. 2017

Molecular and Cellular Biology

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“…To test whether ectopic TGF-β signaling inhibited hPSC-SMPCs from forming more mature myotubes, we measured embryonic (MYH3), fetal (MYH8), and adult (MYH1) myosins at both the RNA and protein levels 40 . We found without TGF-βi, hPSC-myotubes predominately expressed embryonic and fetal myosins.…”

Section: Resultsmentioning

confidence: 99%

ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs

et al. 2017

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Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite cells remains unclear. HPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Utilizing RNA-SEQ, we identified cell surface receptors ERBB3 and NGFR that demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of TGF-β signaling during differentiation improved fusion efficiency, ultrastructural organization, and expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibers after engraftment of CRISPR/Cas9-corrected Duchenne muscular dystrophy hiPSC-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels equal to directly-isolated human fetal muscle cells.

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“…In human fast-twitch muscle, MHC-IIb is present only in a very small subset of specialized muscle, but is observed to re-activate in limb muscle undergoing regeneration after profound degeneration (242). As seen in cardiac muscle, re-expression of fetal myosins occurs in regenerating muscle and during disease (e.g., hypothyroidism) [reviewed in (610)].…”

Section: Sarcomere—the Basic Contractile Unit Of Striated Musclementioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

234

193

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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Developmental myosins: expression patterns and functional significance

Cited by 411 publications

References 111 publications

Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro

Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro

ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs

Overview of the Muscle Cytoskeleton

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