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Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning
Journal article   Open access   Peer reviewed

Myokine Musclin Is Critical for Exercise-Induced Cardiac Conditioning

Matthew P Harris, Shemin Zeng, Zhiyong Zhu, Vitor A Lira, Liping Yu, Denice M Hodgson-Zingman and Leonid V Zingman
International journal of molecular sciences, Vol.24(7), 6525
03/30/2023
DOI: 10.3390/ijms24076525
PMCID: PMC10095193
PMID: 37047496
url
https://doi.org/10.3390/ijms24076525View
Published (Version of record) Open Access

Abstract

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic "crosstalk" to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, , had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and -KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection.
 Heart Animals Gene Expression Regulation Heart Diseases - metabolism Ischemia - metabolism Mice Muscle Proteins - genetics Muscle Proteins - metabolism Muscle, Skeletal - metabolism Physical Conditioning, Animal - physiology Transcription Factors - genetics Transcription Factors - metabolism

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