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Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38\u03b1, p38\u03b2, p38\u03b3, and p38\u03b4) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38\u03b1 activation while causing MKK3-p38\u03b3\/\u03b4 hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38\u03b3 or p38\u03b4 or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3\/6-p38\u03b3\/\u03b4 pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38\u03b1 inhibitors in the long-term treatment since they might result in cardiotoxicity.<\/jats:p>","DOI":"10.7554\/elife.75250","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T10:15:12Z","timestamp":1657534512000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.75250","source":"Crossref","is-referenced-by-count":28,"title":["MKK6 deficiency promotes cardiac dysfunction through MKK3-p38\u03b3\/\u03b4-mTOR hyperactivation"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3935-2647","authenticated-orcid":true,"given":"Rafael","family":"Romero-Becerra","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02qs1a797","id-type":"ROR","asserted-by":"publisher"}],"name":"Centro Nacional de Investigaciones 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