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Lkb1 - Muscling onto the Stem Cell Scene

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Review of Lkb1 is indispensable for skeletal muscle development, regeneration and satellite cell homeostasisfrom Stem Cells by Stuart P. Atkinson

Muscle stem cells, so-called satellite cells (SCs), play a major role in muscle regeneration after damage. The normally quiescent SCs activate, proliferate, and then differentiate and fuse into multinuclear myofibers, allowing muscle repair [1]. The pathways which regulate SC function are however still remain to be fully realized. The serine/threonine protein kinase Lkb1, originally identified as a tumor suppressor protein, plays a plethora of roles in various cell types, and studies in adult mice have found that skeletal/cardiac muscle‐specific deletion of Lkb1 can affect exercise performance, insulin sensitivity, glucose uptake and lipid oxidation [2-4], although mice appear to be healthy without muscle atrophy until 30‐50 weeks [3]. Now, in a recent study in Stem Cells, the group of Shihuan Kuang (Purdue University, West Lafayette, IN, USAhave studied the specific deletion of Lkb1 in muscle progenitor cells and the  resulting defective myogenesis and severe myopathy [5].

Quiescent mouse SCs expressed Lkb1, and this expression increased in some myoblasts during proliferation. Using a specific genetic cross, the authors were able to specifically deplete Lkb1 in skeletal muscles and myoblasts, and not in non-skeletal muscle. Resultant muscle related abnormalities, accompanied by lower bodyweight and increased mortality, suggested that the Lkb1 loss mediated developmental and postnatal growth defects on the skeletal muscles (See Figure). The muscle of Lkb1-mice also displayed obvious myopathic traits, including a switch from oxidative to glycolytic respiration. Looking at SCs, the authors found a larger proportion of SCs had exited the quiescent state and had activated and proliferated in resting skeletal muscles in the Lkb1-depleted mice, leading to an increased number of satellite cells.

A further genetic cross was then used to assess the effect of Lkb1 loss specifically in postnatal SCs (to bypass previous developmental and growth defects) in response to the injection of cardiotoxin into skeletal muscle. Lkb1-depleted SCs displayed poor regeneration and lower levels of repair as compared to wild type controls. There was also a higher amount of activated renewing/proliferating SCs in the Lkb1 depleted mice, although the researchers did note a reduced amount of MyoG+ differentiating myoblasts. Furthermore, upon serum withdrawal induced differentiation, Lkb1-depleted myoblasts differentiated and fused less efficiently.

The authors next assessed possible mechanisms by which Lkb1-depletion mediates its effects. Lkb1 phosphorylates and activates AMPK, which then inhibits mTOR [6]. Lkb1 loss in SCs did indeed lead to lower AMPK phosphorylation, and mediated an increase in mTOR activation. Addition of an AMPK activator rescued these effects and restored the growth rate to wild type levels, although this did not rescue the differentiation deficits, suggesting that Lkb1 modifies differentiation through another pathway, such as the phosphorylation and inactivation of GSK‐3β [7]. Lkb1-depleted myoblasts demonstrated reduced levels of phospho-GSK‐3β, suggesting increased activation of GSK‐3β, while the addition of a GSK‐3β inhibitor could rescue the differentiation deficit of Lkb1 myoblasts, also promoting myotube formation.

These findings demonstrate that the tumor suppressor kinase Lkb1 mediates SC homeostasis and is indispensable for skeletal muscle development. While the researchers do not assess the role of Lkb1 in aging SCs, it is tempting to suggest that the pathways discovered herein may represent putative druggable targets to protect against the age-related decline in muscle strength and function. Additionally, this places another important stem cell role on the already impressive CV of Lkb1; further research may uncover whether this protein is a master controller of stem/progenitor characteristics in mammals.

References

  1. Kuang S and Rudnicki MA The emerging biology of satellite cells and their therapeutic potential. Trends Mol Med 2008;14:82-91.
  2. Koh HJ, Arnolds DE, Fujii N, et al. Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Molecular and cellular biology 2006;26:8217-8227.
  3. Thomson DM, Hancock CR, Evanson BG, et al. Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice. Journal of applied physiology 2010;108:1775-1785.
  4. Jeppesen J, Maarbjerg SJ, Jordy AB, et al. LKB1 regulates lipid oxidation during exercise independently of AMPK. Diabetes 2013;62:1490-1499.
  5. Shan T, Zhang P, Liang X, et al. Lkb1 is indispensable for skeletal muscle development, regeneration and satellite cell homeostasis. Stem Cells 2014;n/a-n/a.
  6. Lizcano JM, Goransson O, Toth R, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. The EMBO journal 2004;23:833-843.
  7. Asada N and Sanada K LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30:8852-8865.