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Saraf-dependent activation of mTORC1 regulates cardiac growth

Pathological cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signaling pathways regulating intracellular Ca2+ homeostasis that control adaptive and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the...

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Main Authors: Sanlialp, Ayse (Author) , Schumacher, Dagmar (Author) , Kiper, Leon (Author) , Varma, Eshita (Author) , Riechert, Eva (Author) , Ho, Thanh Cao (Author) , Sandmann, Christoph (Author) , Kmietczyk, Vivien (Author) , Zimmermann, Frank (Author) , Dlugosz, Sascha (Author) , Wirth, Angela (Author) , Górska, Aga (Author) , Burghaus-Zhang, Jana (Author) , Camacho Londoño, Juan Eduardo (Author) , Katus, Hugo (Author) , Doroudgar, Shirin (Author) , Freichel, Marc (Author) , Völkers, Mirko (Author)
Format: Article (Journal)
Language:English
Published: 13 March 2020
In: Journal of molecular and cellular cardiology
Year: 2020, Volume: 141, Pages: 30-42
ISSN:1095-8584
DOI:10.1016/j.yjmcc.2020.03.004
Online Access:Verlag, lizenzpflichtig, Volltext: https://dx.doi.org/10.1016/j.yjmcc.2020.03.004
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0022282820300596
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Author Notes:Ayse Sanlialp, Dagmar Schumacher, Leon Kiper, Eshita Varma, Eva Riechert, Thanh Cao Ho, Christoph Hofmann, Vivien Kmietczyk, Frank Zimmermann, Sascha Dlugosz, Angela Wirth, Agnieszka A. Gorska, Jana Burghaus, Juan E. Camacho Londoño, Hugo A. Katus, Shirin Doroudgar, Marc Freichel, Mirko Völkers
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Summary:Pathological cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signaling pathways regulating intracellular Ca2+ homeostasis that control adaptive and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the store-operated calcium entry-associated regulatory factor (Saraf), encoded by the Tmem66 gene, on cardiac growth control in vitro and in vivo. Saraf is a single-pass membrane protein located at the sarco/endoplasmic reticulum and regulates intracellular calcium homeostasis. We found that Saraf expression was upregulated in the hypertrophied myocardium and was sufficient for cell growth in response to neurohumoral stimulation. Increased Saraf expression caused cell growth, which was associated with dysregulation of calcium-dependent signaling and sarcoplasmic reticulum calcium content. In vivo, Saraf augmented cardiac myocyte growth in response to angiotensin II and resulted in increased cardiac remodeling together with worsened cardiac function. Mechanistically, Saraf activated mTORC1 (mechanistic target of rapamycin complex 1) and increased protein synthesis, while mTORC1 inhibition blunted Saraf-dependent cell growth. In contrast, the hearts of Saraf knockout mice and Saraf-deficient myocytes did not show any morphological or functional alterations after neurohumoral stimulation, but Saraf depletion resulted in worsened cardiac function after acute pressure overload. SARAF knockout blunted transverse aortic constriction cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for SARAF in compensatory myocyte growth. Collectively, these results reveal a novel link between sarcoplasmic reticulum calcium homeostasis and mTORC1 activation that is regulated by Saraf.
Item Description:Gesehen am 07.10.2020
Physical Description:Online Resource
ISSN:1095-8584
DOI:10.1016/j.yjmcc.2020.03.004

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