Deletion of the Ste20-like kinase SLK in skeletal muscle results in a progressive myopathy and muscle weakness

abstract: ...Background The Ste20-like kinase, SLK, plays an important role in cell proliferation and cytoskeletal remodeling. In fibroblasts, SLK has been shown to respond to FAK/Src signaling and regulate focal adhesion turnover through Paxillin phosphorylation. Full-length SLK has also been shown to be essential for embryonic development. In myoblasts, the overexpression of a dominant negative SLK is sufficient to block myoblast fusion. Methods In this study, we crossed the Myf5-Cre mouse model with our conditional SLK knockout model to delete SLK in skeletal muscle. A thorough analysis of skeletal muscle tissue was undertaken in order to identify defects in muscle development caused by the lack of SLK. Isometric force analysis was performed on adult knockout mice and compared to age-matched wild-type mice. Furthermore, cardiotoxin injections were performed followed by immunohistochemistry for myogenic markers to assess the efficiency muscle regeneration following SLK deletion. Results We show here that early deletion of SLK from the myogenic lineage does not markedly impair skeletal muscle development but delays the regenerative process. Interestingly, adult mice (~6months) display an increase in the proportion of central nuclei and increased p38 activation. Furthermore, mice as young as 3months old present with decreased force generation, suggesting that the loss of SLK impairs myofiber stability and function. Assessment of structural components revealed aberrant localization of focal adhesion proteins, such as FAK and paxillin. Our data show that the loss of SLK results in unstable myofibers resulting in a progressive myopathy. Additionally, the loss of SLK resulted in a delay in muscle regeneration following cardiotoxin injections. Conclusions Our results show that SLK is dispensable for muscle development and regeneration but is required for myofiber stability and optimal force generation. Electronic supplementary material The online version of this article (doi:10.1186/s13395-016-0119-1) contains supplementary material, which is available to authorized users.

...Skelet Muscle Skelet Muscle Skeletal Muscle 2044-5040 BioMed Central London 28153048 5288853 119 10.1186/s13395-016-0119-1 Research Deletion of the Ste20-like kinase SLK in skeletal muscle results in a progressive myopathy and muscle weakness Pryce Benjamin R. bpryce89@gmail.com 1 2 Al-Zahrani Khalid N. Khalid.alza@gmail.com 1 2 Dufresne Sbastien sebastien.dufresne.1@ulavak.ca 3 Belkina Natalya belkinan@yahoo.com 5 Labrche Cdrik clabr023@uottawa.ca 1 2 Patino-Lopez Genaro gena23pat@yahoo.com 6

... Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Background The Ste20-like kinase, SLK, plays an important role in cell proliferation and cytoskeletal remodeling. In fibroblasts, SLK has been shown to respond to FAK/Src signaling and regulate focal adhesion turnover through Paxillin phosphorylation. Full-length SLK has also been shown to be essential for embryonic development. In myoblasts, the overexpression of a dominant negative SLK is sufficient to block myoblast fusion. Methods In this study, we crossed the Myf5-Cre mouse model with our conditional SLK knockout model to delete SLK in skeletal muscle. A thorough analysis of skeletal muscle tissue was undertaken in order to identify defects in muscle development caused by the lack of SLK. Isometric force analysis was performed on adult knockout mice and compared to age-matched wild-type mice. Furthermore, cardiotoxin injections were performed followed by immunohistochemistry for myogenic markers to assess the efficiency muscle regeneration following SLK deletion. Results We show here that early deletion of SLK from the myogenic lineage does not markedly impair skeletal muscle development but delays the regenerative process. Interestingly, adult mice (~6months) display an increase in the proportion of central nuclei and increased p38 activation. Furthermore, mice as young as 3months old present with decreased force generation, suggesting that the loss of SLK impairs myofiber stability and function. Assessment of structural components revealed aberrant localization of focal adhesion proteins, such as FAK and paxillin. Our data show that the loss of SLK results in unstable myofibers resulting in a progressive myopathy. Additionally, the loss of SLK resulted in a delay in muscle regeneration following cardiotoxin injections. Conclusions Our results show that SLK is dispensable for muscle development and regeneration

...-nucleated myotubes [ 19 , 20 ]. Interestingly, downstream components of the integrin signaling system, such as FAK and paxillin, are also upregulated in hypertrophied muscles, suggesting that they are beneficial for muscle growth and function [ 21 ]. The Ste20-like kinase (SLK) is a ubiquitously expressed protein found at high levels in developing myogenic and neuronal tissues [ 22 , 23 ]. Full-length SLK consists of an N-terminal catalytic kinase domain, a coiled-coiled region and a disorganized C-terminal region termed the ATH domain [ 24 , 25 ]. The ATH region has been shown to bind Ldb1 and LMO4, both of which act to modulate SLK kinase activity [ 26 , 27 ]. We have shown that SLK is activated downstream of the integrin/FAK/Src signaling system to mediate cellular migration and focal adhesion turnover through paxillin phosphorylation [ 28 , 29 ]. SLK also functions upstream of RhoA-GTPase to regulate the formation actin stress fibers in smooth muscle cells [ 30 ]. Expression of a dominant

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Gene: SLK - STE20-like kinase - (NCBI)

Protein : 2uv2

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