Abstract
With-no-lysine (K) (WNK) kinases, which are mutated in the inherited form of hypertension pseudohypoaldosteronism type II, are essential regulators of membrane ion transporters. Here, we report that WNK1 positively regulates skeletal muscle cell hypertrophy via mediating the function of the pro-longevity transcription factor forkhead box protein O4 (FOXO4) independent of the conventional WNK signaling pathway linking SPS/STE20-related proline-alanine–rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1) to downstream effector ion transporters. Small interfering RNA (siRNA)-mediated silencing of WNK1, but not SPAK/OSR1 kinases, induced myotube atrophy and remarkable increases in the mRNA expression of the muscle atrophy ubiquitin ligases MAFbx and MuRF1 in C2C12 mouse skeletal muscle cells. WNK1 silencing also increased FOXO4 nuclear localization, and co-transfection of Foxo4-targeted siRNA completely reversed the myotube atrophy and upregulation of atrogene transcription induced by WNK1 silencing. We further illustrated that WNK1 protein abundance in skeletal muscle was increased by chronic voluntary wheel running exercise (hypertrophic stimulus) and markedly decreased by adenine-induced chronic kidney disease (atrophic stimulus) in mice. These findings suggest that WNK1 is involved in the physiological regulation of mammalian skeletal muscle hypertrophy and atrophy via interactions with FOXO4. The WNK1-FOXO4 axis may be a potential therapeutic target in human diseases causing sarcopenia.
Highlights
Skeletal muscle is the largest tissue in the human body, comprising 40–50% of body mass
To clarify whether WNK1 is expressed in mouse C2C12 skeletal muscle cells and muscle tissue, we examined WNK1–4 mRNA levels in C2C12 cells and various tissues via reverse transcription (RT)-PCR, as well as WNK1 protein levels in differentiating C2C12 cells via Western blotting
The present study demonstrated that WNK1 kinase, the protein abundance of which is increased during myoblast differentiation into myotubes, positively controls myotube hypertrophy
Summary
Skeletal muscle is the largest tissue in the human body, comprising 40–50% of body mass This essential tissue functions as an endocrine organ, regulating metabolic homeostasis. We investigated the role of WNK kinases in skeletal muscle hypertrophy with a specific focus on WNK1 because of its abundant expression in mammalian skeletal muscles[20] and a recent report of a family with limb-girdle muscular dystrophy caused by a WNK1 mutation[21]. We demonstrated that WNK1 positively regulates muscle hypertrophy in C2C12 mouse skeletal muscle cells This effect was attributable to a previously unrecognized link between WNK1 and the pro-longevity transcription factor forkhead box protein O4 (FOXO4), which regulates lifespan extension, tumor suppression, and energy metabolism[22]
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