FOS licenses early events in stem cell activation driving skeletal muscle regeneration

SUMMARYTissue regeneration requires the selective activation and repression of specific signaling pathways in stem cells. As such, the Wnt signaling pathways have been shown to control stem cell fate. In many cell types, the R-Spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. Firstly we show that Rspo1-null muscles do not display any abnormalities at the basal level. However deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle stem cells lacking Rspo1 show delayed differentiation. Transcriptome analysis further demonstrated that Rspo1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking Rspo1 fuse with a higher frequency than normal cells, leading to larger myotubes containing more nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that antagonistic control of canonical and non-canonical Wnt signaling pathways by Rspo1 in muscle stem cell progeny is important for restitution of normal muscle architecture during skeletal muscle regeneration.

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CHD4 ensures stem cell lineage fidelity during skeletal muscle regeneration

Stem Cell Reports ◽

10.1016/j.stemcr.2021.07.022 ◽

2021 ◽

Vol 16 (9) ◽

pp. 2089-2098

Author(s):

Krishnamoorthy Sreenivasan ◽

Alejandra Rodríguez-delaRosa ◽

Johnny Kim ◽

Diana Mesquita ◽

Jessica Segalés ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cell ◽

Muscle Regeneration ◽

Cell Lineage ◽

Skeletal Muscle Regeneration ◽

Stem Cell Lineage

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Krüppel like factor 2 - deficient myeloid cells promote skeletal muscle regeneration after injury

10.1101/312868 ◽

2018 ◽

Author(s):

Palanikumar Manoharan ◽

Taejeong Song ◽

Tatiana L Radzyukevich ◽

Sakthivel Sadayappan ◽

Jerry B Lingrel ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Cell Activation ◽

Myeloid Cells ◽

Myeloid Cell ◽

Innate Immune ◽

Skeletal Muscle Regeneration ◽

Adult Skeletal Muscle ◽

Complex Interactions ◽

Elevated Expression

Regeneration of adult skeletal muscle after injury is coordinated by complex interactions between the injured muscle and the innate immune system. Myeloid lineage cells predominate in this process. This study examined the role of Krüppel like factor 2 (KLF2), a zinc-finger transcription factor that regulates myeloid cell activation state, in muscle regeneration. Gastrocnemius muscles of wild-type and myeKlf2-/- mice, which lack KLF2 in all myeloid cells, were subjected to cardiotoxin injury and followed for 21 days. Injured muscles of myeKlf2-/- contained more infiltrating, inflammatory Ly6C+ monocytes, with elevated expression of inflammatory mediators. Infiltrating monocytes matured earlier into pro-inflammatory macrophages with phenotype Ly6C+, CD11b+, F4/80+. Inflammation resolved earlier and progressed to myogenesis, marked by an earlier decline of Ly6C+ macrophages and their replacement with anti-inflammatory Ly6C- populations, in association with elevated expression of factors that resolve inflammation and promote myogenesis. Overall, regeneration was completed earlier. These findings identify myeloid KLF2 as a central regulator of the innate immune response to acute skeletal muscle injury. Manipulating myeloid KLF2 levels may be a useful strategy for accelerating regeneration.

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