Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength

Bentzinger, C. Florian; Maltzahn, Julia von; Dumont, Nicolas A.; Stark, Danny A.; Wang, Yu Xin; Nhan, Kevin; Frenette, Jérôme; Cornelison, D.D.W.; Rudnicki, Michael A.

doi:10.1083/jcb.201310035

Cited by 138 publications

(131 citation statements)

References 41 publications

(72 reference statements)

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“…42 During development, there is dramatic migration of muscle precursors during the initial formation of muscle, and incorporation of satellite cells into damaged muscle can occur at sites distant from the injury. 38,43 Surprisingly, knockout of nesprin-2 in mice does not lead to developmental defects, suggesting either that the migration of muscle precursors during development differs from that of myoblasts derived from satellite cells during muscle repair or that there are redundant factors that come into play during development.…”

Section: Discussionmentioning

confidence: 99%

Linker of nucleoskeleton and cytoskeleton (LINC) complex-mediated actin-dependent nuclear positioning orients centrosomes in migrating myoblasts

Chang¹,

Antoku

Östlund

et al. 2015

Nucleus

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Abbreviations: CH, calponin homology; EDMD, Emery-Dreifuss muscular dystrophy; GFP, green fluorescent protein; GFP-mN2G, GFP-mini-nesprin-2G; LINC, linker of nucleoskeleton and cytoskeleton; LPA, lysophosphatidic acid; TAN lines, transmembrane actin-associated nuclear lines.Myoblast migration is essential for muscle development and repair; however, the factors that contribute to the polarity of migrating myoblasts are relatively unknown. We find that randomly migrating C2C12 myoblasts orient their centrosomes in the direction of migration. Using wounded monolayers, we further show that centrosome orientation is stimulated by the serum factor lysophosphatidic acid (LPA) and involves the rearward movement of the nucleus while the centrosome is maintained at the cell centroid. The rate of nuclear movement correlated with that of actin retrograde flow and both cytochalasin D and blebbistatin prevented nuclear movement and centrosome orientation. Actin-dependent rearward nuclear movement in fibroblasts is mediated by assembly of nuclear membrane nesprin-2G and SUN2 LINC complexes into transmembrane actin-associated nuclear (TAN) lines anchored by A-type lamins and emerin. In C2C12 myoblasts, depletion of nesprin-2G, SUN2 or lamin A/C prevented nuclear movement and endogenous nesprin-2G and a chimeric GFP-mini-nesprin-2G formed TAN lines during nuclear movement. Depleting nesprin-2G strongly interfered with directed cell migration and reduced the efficiency of myoblast fusion into multinucleated myotubes. Our results show that nuclear movement contributes to centrosome orientation and polarity for efficient migration and fusion of myoblasts. Given that mutations in the genes encoding A-type lamins, nesprin-2 and SUN2 cause Emery-Dreifuss muscular dystrophy and related myopathies, our results have implications for understanding the mechanism of disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Linker of nucleoskeleton and cytoskeleton (LINC) complex-mediated actin-dependent nuclear positioning orients centrosomes in migrating myoblasts

Chang¹,

Antoku

Östlund

et al. 2015

Nucleus

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“…In mice, the increase in satellite cell number and fiber size has been shown to be related to Wnt signaling activated by Wnt binding to Frizzled receptors. Wnt signaling involves a Wnt/ β-catenin and a Wnt/planar cell polarity pathway and is further linked to the Akt/mTOR axis (Bentzinger et al, 2014). The second major pathway involved in satellite cell proliferation and differentiation is the Notch pathway activated by the ligand Delta.…”

Section: Activation Of Satellite Cellsmentioning

confidence: 99%

Molecular networks in skeletal muscle plasticity

Hoppeler

2016

Journal of Experimental Biology

163

117

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The skeletal muscle phenotype is subject to considerable malleability depending on use as well as internal and external cues. In humans, low-load endurance-type exercise leads to qualitative changes of muscle tissue characterized by an increase in structures supporting oxygen delivery and consumption, such as capillaries and mitochondria. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In endurance exercise, stress-induced signaling leads to transcriptional upregulation of genes, with Ca 2+ signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several interrelated signaling pathways converge on the transcriptional co-activator PGC-1α, perceived to be the coordinator of much of the transcriptional and post-transcriptional processes. Strength training is dominated by a translational upregulation controlled by mTORC1. mTORC1 is mainly regulated by an insulin-and/or growth-factor-dependent signaling cascade as well as mechanical and nutritional cues. Muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. In addition, there are several negative regulators of muscle mass. We currently have a good descriptive understanding of the molecular mechanisms controlling the muscle phenotype. The topology of signaling networks seems highly conserved among species, with the signaling outcome being dependent on the particular way individual species make use of the options offered by the multi-nodal networks. As a consequence, muscle structural and functional modifications can be achieved by an almost unlimited combination of inputs and downstream signaling events.

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“…Although the use of mdx mice for providing insight regarding human DMD has generated considerable debate within the scientific community, it remains an invaluable experimental model. Indeed, over the last 30 years, many elegant papers have been published on the mdx mouse, including studies in which several therapeutic strategies have been analyzed [25][26][27][28][29][30][31][32].…”

Section: Animal Models Of Muscular Dystrophymentioning

confidence: 99%

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Forcina

Pelosi

Miano

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which the dystrophin gene is mutated, resulting in dysfunctional dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. Moreover, the imbalance between muscle damage and repair leads to a chronic inflammatory response and an increase in the amount of fibrosis over time. The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. In this review, we analyze the pathogenic role of both inflammation and oxidative stress in muscular dystrophy.

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Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength

Abstract: In addition to stimulating skeletal muscle growth and repair, Wnt7a/Fzd7 signaling increases the polarity and directional migration of myogenic progenitors and improves the efficacy of muscle stem cell therapy.

Cited by 138 publications

References 41 publications

Linker of nucleoskeleton and cytoskeleton (LINC) complex-mediated actin-dependent nuclear positioning orients centrosomes in migrating myoblasts

Linker of nucleoskeleton and cytoskeleton (LINC) complex-mediated actin-dependent nuclear positioning orients centrosomes in migrating myoblasts

Molecular networks in skeletal muscle plasticity

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

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