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Updated: Jul 2, 2025
Isolation, Culture and Transduction of Adult Mouse Cardiomyocytes
Published on: August 28, 2016
Myoglobin modulates the Hippo pathway to promote cardiomyocyte differentiation
Krithika Rao1, Elizabeth Rochon1, Anuradha Singh1
1Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Insights
Myoglobin drives cardiomyocyte differentiation by regulating the Hippo pathway. Myoglobin deficiency impairs differentiation but enhances cardiac regeneration in zebrafish and mice.
Area of Science:
- Cardiovascular Biology
- Cellular Differentiation
- Regenerative Medicine
Background:
- Endogenous mechanisms of cardiomyocyte differentiation are not fully understood.
- Myoglobin expression increases during cardiomyocyte differentiation, but its role is unknown.
Purpose of the Study:
- To investigate the role of myoglobin in cardiomyocyte differentiation and cardiac regeneration.
- To elucidate the molecular mechanisms by which myoglobin regulates these processes.
Main Methods:
- Utilized cardiomyocyte models, myoglobin-deficient zebrafish, and murine heart studies.
- Assessed gene expression of differentiation markers, cellular proliferation, and Hippo pathway signaling (LATS1, YAP).
Main Results:
- Myoglobin deletion in vitro decreased differentiation markers and increased proliferation.
- Myoglobin deficiency in vivo led to YAP dephosphorylation and accelerated cardiac regeneration in zebrafish.
- Myoglobin knockdown in neonatal mice also resulted in YAP dephosphorylation and increased cardiomyocyte cycling.
Conclusions:
- Myoglobin acts as an endogenous driver of cardiomyocyte differentiation.
- Myoglobin's heme group regulates the Hippo pathway via LATS1 and YAP.
- Myoglobin is a potential therapeutic target for enhancing cardiac development and regeneration.
Abstract:
The endogenous mechanisms that propagate cardiomyocyte differentiation and prevent de-differentiation remain unclear. While the expression of the heme protein myoglobin increases by over 50% during cardiomyocyte differentiation, a role for myoglobin in regulating cardiomyocyte differentiation has not been tested. Here, we show that deletion of myoglobin in cardiomyocyte models decreases the gene expression of differentiation markers and stimulates cellular proliferation, consistent with cardiomyocyte de-differentiation. Mechanistically, the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, resulting in phosphorylation and inactivation of yes-associated protein (YAP). In vivo, myoglobin-deficient zebrafish hearts show YAP dephosphorylation and accelerated cardiac regeneration after apical injury. Similarly, myoglobin knockdown in neonatal murine hearts shows increased YAP dephosphorylation and cardiomyocyte cycling. These data demonstrate a novel role for myoglobin as an endogenous driver of cardiomyocyte differentiation and highlight myoglobin as a potential target to enhance cardiac development and improve cardiac repair and regeneration.
