MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
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Evaluation Summary:
This paper demonstrates that deletion of MKK6 reduces life span in mice, and leads to cardiac hypertrophy that progresses to cardiac dilatation and fibrosis with age. The authors also demonstrate that the mechanism for this phenomenon is through reduced p38a activation while causing MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The authors extend previous studies (that demonstrate a role for P38 proteins as downstream effector of MKK6) and identify the isoform of P38 that plays a role in this process. Overall, the studies in this paper are conducted carefully and most of the conclusions are based on the reported data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) 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 p38α activation while causing MKK3-p38γ/δ 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 p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.
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Evaluation Summary:
This paper demonstrates that deletion of MKK6 reduces life span in mice, and leads to cardiac hypertrophy that progresses to cardiac dilatation and fibrosis with age. The authors also demonstrate that the mechanism for this phenomenon is through reduced p38a activation while causing MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The authors extend previous studies (that demonstrate a role for P38 proteins as downstream effector of MKK6) and identify the isoform of P38 that plays a role in this process. Overall, the studies in this paper are conducted carefully and most of the conclusions are based on the reported data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The …
Evaluation Summary:
This paper demonstrates that deletion of MKK6 reduces life span in mice, and leads to cardiac hypertrophy that progresses to cardiac dilatation and fibrosis with age. The authors also demonstrate that the mechanism for this phenomenon is through reduced p38a activation while causing MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The authors extend previous studies (that demonstrate a role for P38 proteins as downstream effector of MKK6) and identify the isoform of P38 that plays a role in this process. Overall, the studies in this paper are conducted carefully and most of the conclusions are based on the reported data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
In this paper, Romero-Becerra et al report their findings on MKK6 deficiency in the heart. They show that global deletion of MKK6 reduces life span in mice. They also show that young mice have cardiac hypertrophy and that it progresses to cardiac dilatation and fibrosis as they age. Their mechanistic studies demonstrate that MKK6 deletion leads to reduced p38a activation but at the same time causes MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The activation of this pathway then results in cardiac hypertrophy. To confirm the role of this pathway, they show that cardiac hypertrophy in Mkk6-/- mice is reversed with deletion of either p38g or p38d, or with rapamycin treatment. They also demonstrate similar findings in cardiac specific MKK6 KO mice. They conclude that they have identified "a key …
Reviewer #1 (Public Review):
In this paper, Romero-Becerra et al report their findings on MKK6 deficiency in the heart. They show that global deletion of MKK6 reduces life span in mice. They also show that young mice have cardiac hypertrophy and that it progresses to cardiac dilatation and fibrosis as they age. Their mechanistic studies demonstrate that MKK6 deletion leads to reduced p38a activation but at the same time causes MKK3-p38g/d hyperphosphorylation and increased mTOR signaling. The activation of this pathway then results in cardiac hypertrophy. To confirm the role of this pathway, they show that cardiac hypertrophy in Mkk6-/- mice is reversed with deletion of either p38g or p38d, or with rapamycin treatment. They also demonstrate similar findings in cardiac specific MKK6 KO mice. They conclude that they have identified "a key role for the MKK3/6-p38g/d pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38a inhibitors in the long-term treatment since they might result in cardiotoxicity".
This paper is interesting and the experiments are conducted carefully. However, a lot is already known about MKK proteins and their downstream targets P38 proteins. For example, Martindale et al in 2005 showed that overexpression of MKK6 in the heart proteins protects against MI (J Biol Chem. 2005 Jan 7;280(1):669-76). This paper is not even referenced in the manuscript. Additionally, a lot is known about the effects of MKK6 on P38 proteins, but the authors fail to highlight the novelty of their paper over previously published papers. Additionally, some of the experiments are not carefully conducted or interpreted and additional experiments or explanation is needed for those figures.
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Reviewer #2 (Public Review):
In this manuscript, Romero-Becerra et al. utilize molecular biology techniques to fill a key gap in the field - how different p38 MAPK isoforms are regulated, as well as the contributions of MKK3 and MKK6 to cardiac hypertrophy. The strengths of the paper include the generation and characterization of multiple novel mouse models for in vivo modulation the MKK3/6-p38 signaling pathway. The work has implications for the clinical use of p38a inhibitors and is likely to be highly impactful in the field of cardiovascular mTOR biology.
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Reviewer #3 (Public Review):
This study demonstrates that 9-week-old mice with systemic MKK6 gene deletion exhibit cardiac hypertrophy with preserved cardiac function. Similar results were observed in mice with cardiomyocyte-restricted MKK6 gene deletion. On the other hand, aged MKK6 -/- mice progressively develop cardiac dysfunction and fibrosis. Deletion of the MKK6 gene leads to decreased p38α phosphorylation and increased MKK3/p38γ/δ pathway activation. The latter is associated with mTOR overactivation and protein synthesis. Concomitant deletion of p38γ or p38δ, as well as inhibition of mTOR with rapamycin, rescue hypertrophy in 9-week-old MKK6 -/- mice.
In general, this paper is interesting. The demonstration of a crosstalk between MKK6 and 3 involving p38 isoforms and mTOR is intriguing. However, there are some important issues …
Reviewer #3 (Public Review):
This study demonstrates that 9-week-old mice with systemic MKK6 gene deletion exhibit cardiac hypertrophy with preserved cardiac function. Similar results were observed in mice with cardiomyocyte-restricted MKK6 gene deletion. On the other hand, aged MKK6 -/- mice progressively develop cardiac dysfunction and fibrosis. Deletion of the MKK6 gene leads to decreased p38α phosphorylation and increased MKK3/p38γ/δ pathway activation. The latter is associated with mTOR overactivation and protein synthesis. Concomitant deletion of p38γ or p38δ, as well as inhibition of mTOR with rapamycin, rescue hypertrophy in 9-week-old MKK6 -/- mice.
In general, this paper is interesting. The demonstration of a crosstalk between MKK6 and 3 involving p38 isoforms and mTOR is intriguing. However, there are some important issues that need to be addressed. In some cases, data are associative and additional experiments are needed to better dissect the molecular mechanisms underlying the cardiac effects of MKK6 gene deletion. In particular, it is not clear whether MKK6 restrains cardiac growth by MKK3 inhibition or p38α activation. Additional experiments are needed to clarify the molecular mechanisms through which p38γ/δ and mTOR are activated in MKK6 -/- mice. Cause of death in MKK6 -/- mice should also be studied.
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