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



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.



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 (~6 months) display an increase in the proportion of central nuclei and increased p38 activation. Furthermore, mice as young as 3 months 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.



Our results show that SLK is dispensable for muscle development and regeneration but is required for myofiber stability and optimal force generation.
Department of Cellular and Molecular Medicine, Faculty of Medicine,, University of Ottawa, Ottawa, ON Canada.|Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Rd, BOX 926, Ottawa, ON Canada.
Benjamin R
BR
Pryce
Department of Cellular and Molecular Medicine, Faculty of Medicine,, University of Ottawa, Ottawa, ON Canada.|Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Rd, BOX 926, Ottawa, ON Canada.
Khalid N
KN
Al-Zahrani
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de L'Université Laval, Université Laval, Quebec City, Canada.
Sébastien
S
Dufresne
National Cancer Institute at the National Institutes of Health, Bethesda, MD USA.
Natalya
N
Belkina
Department of Cellular and Molecular Medicine, Faculty of Medicine,, University of Ottawa, Ottawa, ON Canada.|Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Rd, BOX 926, Ottawa, ON Canada.
Cédrik
C
Labrèche
Laboratorio de Investigación en Inmunología y Proteómica Hospital Infantil de México "Federico Gómez", México, Distrito Federal México.
Genaro
G
Patino-Lopez
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de L'Université Laval, Université Laval, Quebec City, Canada.|Département de Réadaptation, Faculté de Médecine, Université Laval, Quebec City, Canada.
Jérôme
J
Frenette
National Cancer Institute at the National Institutes of Health, Bethesda, MD USA.
Stephen
S
Shaw
Department of Cellular and Molecular Medicine, Faculty of Medicine,, University of Ottawa, Ottawa, ON Canada.|Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Rd, BOX 926, Ottawa, ON Canada.
Luc A
LA
Sabourin
D000818:Animals; D002478:Cells, Cultured; D022001:Focal Adhesions / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051419:Paxillin / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012038:Regeneration; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099317:Hippo Kinases
D051419:Paxillin; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C402650:SLK protein, mouse; D000099317:Hippo Kinases
Muscle regeneration; Myofiber stability; Ste20-like kinase