2019 Fiscal Year Final Research Report
Identification and functional analysis of WNK kinase signaling in skeletal muscle hypertrophy
Project/Area Number |
19K21299
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Project/Area Number (Other) |
18H06194 (2018)
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund (2019) Single-year Grants (2018) |
Review Section |
0902:General internal medicine and related fields
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Mandai Shintaro 東京医科歯科大学, 医学部附属病院, 特任助教 (50824330)
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Project Period (FY) |
2018-08-24 – 2020-03-31
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Keywords | 骨格筋 / WNKキナーゼ / シグナル伝達 / 慢性腎臓病 / サルコペニア / WNK / 腎臓 / リン酸化 |
Outline of Final Research Achievements |
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 revealed that WNK1 positively regulates skeletal muscle hypertrophy via modulating the function of the pro-longevity transcription factor forkhead box protein O4 (FOXO4). In C2C12 mouse skeletal muscle cells, small interfering RNA (siRNA)-mediated silencing of WNK1 or a WNK kinase inhibitor WNK463 induced myotube atrophy and remarkable increases in the mRNA expression of the muscle atrophy ubiquitin ligases MAFbx and MuRF1, by decreasing phosphorylation and increasing nuclear localization of FOXO4. We further showed that WNK1 protein abundance in skeletal muscle was increased by chronic exercise (hypertrophic stimulus) and decreased by adenine-induced chronic kidney disease (atrophic stimulus) in mice. The WNK1-FOXO4 axis may be a potential therapeutic target in human diseases causing sarcopenia.
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Free Research Field |
分子細胞生物学、腎臓病学、内科学
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Academic Significance and Societal Importance of the Research Achievements |
サルコペニア(加齢, 慢性疾患による骨格筋量・筋力の低下)の病態解明は未だに不十分であり,運動療法,食事療法以外の治療戦略の開発が医療経済的観点からも喫緊の課題である。本研究は,慢性腎臓病・サルコペニアモデルマウスの骨格筋におけるWNK1タンパク発現量の低下,筋萎縮関連遺伝子群の転写亢進をも見出し,WNK1-FOXO4シグナルがヒトのサルコペニアの発症機序の一端を担う可能性を示した。本邦でも高齢者の約5人に1人,重症の慢性腎臓病患者においては約2人に1人がサルコペニアを合併することが知られる。今後の研究でWNK1-FOXO4シグナルをターゲットとした新たな治療戦略を創出するを目指したい。
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