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Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis.

ABSTRACT: Serine/threonine kinase 11, commonly known as liver kinase b1 (Lkb1), is a tumor suppressor that regulates cellular energy metabolism and stem cell function. Satellite cells are skeletal muscle resident stem cells that maintain postnatal muscle growth and repair. Here, we used MyoD(Cre)/Lkb1(flox/flox) mice (called MyoD-Lkb1) to delete Lkb1 in embryonic myogenic progenitors and their descendant satellite cells and myofibers. The MyoD-Lkb1 mice exhibit a severe myopathy characterized by central nucleated myofibers, reduced mobility, growth retardation, and premature death. Although tamoxifen-induced postnatal deletion of Lkb1 in satellite cells using Pax7(CreER) mice bypasses the developmental defects and early death, Lkb1 null satellite cells lose their regenerative capacity cell-autonomously. Strikingly, Lkb1 null satellite cells fail to maintain quiescence in noninjured resting muscles and exhibit accelerated proliferation but reduced differentiation kinetics. At the molecular level, Lkb1 limits satellite cell proliferation through the canonical AMP-activated protein kinase/mammalian target of rapamycin pathway, but facilitates differentiation through phosphorylation of GSK-3?, a key component of the WNT signaling pathway. Together, these results establish a central role of Lkb1 in muscle stem cell homeostasis, muscle development, and regeneration.

SUBMITTER: Shan T

PROVIDER: S-EPMC4198532 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis.

Shan Tizhong T Zhang Pengpeng P Liang Xinrong X Bi Pengpeng P Yue Feng F Kuang Shihuan S

Stem cells (Dayton, Ohio) 20141101 11

Serine/threonine kinase 11, commonly known as liver kinase b1 (Lkb1), is a tumor suppressor that regulates cellular energy metabolism and stem cell function. Satellite cells are skeletal muscle resident stem cells that maintain postnatal muscle growth and repair. Here, we used MyoD(Cre)/Lkb1(flox/flox) mice (called MyoD-Lkb1) to delete Lkb1 in embryonic myogenic progenitors and their descendant satellite cells and myofibers. The MyoD-Lkb1 mice exhibit a severe myopathy characterized by central n ...[more]

PMID: 25069613

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Project description:Skeletal muscle regeneration following injury results from the proliferation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Infiltrating macrophages play an essential role in the process partly by clearing the necrotic cell debris, partly by producing cytokines that guide myogenesis. Infiltrating macrophages are at the beginning pro-inflammatory, but phagocytosis of dead cells induces a phenotypic change to become healing macrophages that regulate inflammation, myoblast fusion and growth, fibrosis, vascularization and return to homeostasis. The TAM receptor kinases Mer and Axl are known efferocytosis receptors in macrophages functioning in tolerogenic or inflammatory conditions, respectively. Here we investigated their involvement in the muscle regeneration process by studying the muscle repair following cardiotoxin-induced injury in Mer-/- mice. We found that Axl was the only TAM kinase receptor expressed on the protein level by skeletal muscle and C2C12 myoblast cells, while Mer was the dominant TAM kinase receptor in the CD45+ cells, and its expression significantly increased during repair. Mer ablation did not affect the skeletal muscle weight or structure, but following injury it resulted in a delay in the clearance of necrotic muscle cell debris, in the healing phenotype conversion of macrophages and consequently in a significant delay in the full muscle regeneration. Administration of the TAM kinase inhibitor BMS-777607 to wild type mice mimicked the effect of Mer ablation on the muscle regeneration process, but in addition, it resulted in a long-persisting necrotic area. Finally, in vitro inhibition of TAM kinase signaling in C2C12 myoblasts resulted in decreased viability and in impaired myotube growth. Our work identifies Axl as a survival and growth receptor in the mouse myoblasts, and reveals the contribution of TAM kinase-mediated signaling to the skeletal muscle regeneration both in macrophages and in myoblasts.

Dataset Information

Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis.

Publications

Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis.

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