Myoglobin modulates the Hippo pathway to promote cardiomyocyte differentiation
Krithika Rao,
Elizabeth Rochon,
Anuradha Singh,
Rajaganapathi Jagannathan,
Zishan Peng,
Haris Mansoor,
Bing Wang,
Mousumi Moulik,
Manling Zhang,
Anita Saraf,
Paola Corti,
Sruti Shiva
Affiliations
Krithika Rao
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
Elizabeth Rochon
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
Anuradha Singh
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
Rajaganapathi Jagannathan
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cardiology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA
Zishan Peng
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Haris Mansoor
Heart and Vascular Institute Division of Cardiology, Department of Medicine and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Bing Wang
Molecular Therapy Lab, Stem Cell Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Mousumi Moulik
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cardiology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA
Manling Zhang
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cardiology, Veteran Affair Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Anita Saraf
Heart and Vascular Institute Division of Cardiology, Department of Medicine and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Paola Corti
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Sruti Shiva
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Corresponding author
Summary: 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.
