Defective BVES-mediated feedback control of cAMP in muscular dystrophy

Haiwen Li, Peipei Wang, Chen Zhang, Yuanbojiao Zuo, Yuan Zhou and Renzhi Han ()
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Haiwen Li: Indiana University School of Medicine
Peipei Wang: Indiana University School of Medicine
Chen Zhang: Indiana University School of Medicine
Yuanbojiao Zuo: Indiana University School of Medicine
Yuan Zhou: Indiana University School of Medicine
Renzhi Han: Indiana University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Biological processes incorporate feedback mechanisms to enable positive and/or negative regulation. cAMP is an important second messenger involved in many aspects of muscle biology. However, the feedback mechanisms for the cAMP signaling control in skeletal muscle are largely unknown. Here we show that blood vessel epicardial substance (BVES) is a negative regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling involved in maintaining muscle mass and function. BVES deletion in mice reduces muscle mass and impairs muscle performance, whereas virally delivered BVES expressed in Bves-deficient skeletal muscle reverses these defects. BVES interacts with and negatively regulates ADCY9’s activity. Disruption of BVES-mediated control of cAMP signaling leads to an increased protein kinase A (PKA) signaling cascade, thereby promoting FoxO-mediated ubiquitin proteasome degradation and autophagy initiation. Our study reveals that BVES functions as a negative feedback regulator of ADCY9-cAMP signaling in skeletal muscle, playing an important role in maintaining muscle homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-37496-8

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