Muscle-specific deletion of SLK/Stk2 enhances p38 activity and myogenesis in mdx mice.

Biochimica et biophysica acta. Molecular cell research 2021 Feb

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Duchenne's muscular dystrophy (DMD) is a severe muscle wasting disorder characterized by the loss of dystrophin expression, muscle necrosis, inflammation and fibrosis. Ongoing muscle regeneration is impaired by persistent cytokine stress, further decreasing muscle function. Patients with DMD rarely survive beyond their early 20s, with cardiac and respiratory dysfunction being the primary cause of death. Despite an increase in our understanding of disease progression as well as promising preclinical animal models for therapeutic intervention, treatment options for muscular dystrophy remain limited and novel therapeutic targets are required. Many reports suggest that the TGFβ signalling pathway is activated in dystrophic muscle and contributes to the pathology of DMD in part by impairing the differentiation of myoblasts into mature myofibers. Here, we show that in vitro knockdown of the Ste20-like kinase, SLK, can partially restore myoblast differentiation downstream of TGFβ in a Smad2/3 independent manner. In an mdx model, we demonstrate that SLK is expressed at high levels in regenerating myofibers. Muscle-specific deletion of SLK reduced leukocyte infiltration, increased myogenin and utrophin expression and enhanced differentiation. This was accompanied by resistance to eccentric contraction-induced injury in slow fiber type-enriched soleus muscles. Finally, we found that these effects were partially dependent on the upregulation of p38 signalling. Collectively, these results demonstrate that SLK downregulation can restore some aspects of disease progression in DMD. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Benjamin R Pryce, Cédrik Labrèche, Dounia Hamoudi, John Abou-Hamad, Khalid N Al-Zahrani, Jonathan J Hodgins, Antoine Boulanger-Piette, Sabrina Bossé, Cindy Balog-Alvarez, Jérôme Frénette, Michele Ardolino, Joe N Kornegay, Luc A Sabourin. Muscle-specific deletion of SLK/Stk2 enhances p38 activity and myogenesis in mdx mice. Biochimica et biophysica acta. Molecular cell research. 2021 Feb;1868(2):118917