Abstract
The desmin-associated protein myospryn, encoded by the cardiomyopathy-associated gene 5 (CMYA5), is a TRIM-like protein associated to the BLOC-1 (Biogenesis of Lysosomes Related Organelles Complex 1) protein dysbindin. Human myospryn mutations are linked to both cardiomyopathy and schizophrenia; however, there is no evidence of a direct causative link of myospryn to these diseases. Therefore, we sought to unveil the role of myospryn in heart and brain. We have genetically inactivated the myospryn gene by homologous recombination and demonstrated that myospryn null hearts have dilated phenotype and compromised cardiac function. Ultrastructural analyses revealed that the sarcomere organization is not obviously affected; however, intercalated disk (ID) integrity is impaired, along with mislocalization of ID and sarcoplasmic reticulum (SR) protein components. Importantly, cardiac and skeletal muscles of myospryn null mice have severe mitochondrial defects with abnormal internal vacuoles and extensive cristolysis. In addition, swollen SR and T-tubules often accompany the mitochondrial defects, strongly implying a potential link of myospryn together with desmin to SR- mitochondrial physical and functional cross-talk. Furthermore, given the reported link of human myospryn mutations to schizophrenia, we performed behavioral studies, which demonstrated that myospryn-deficient male mice display disrupted startle reactivity and prepulse inhibition, asocial behavior, decreased exploratory behavior, and anhedonia. Brain neurochemical and ultrastructural analyses revealed prefrontal-striatal monoaminergic neurotransmitter defects and ultrastructural degenerative aberrations in cerebellar cytoarchitecture, respectively, in myospryn-deficient mice. In conclusion, myospryn is essential for both cardiac and brain structure and function and its deficiency leads to cardiomyopathy and schizophrenia-associated symptoms.
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Acknowledgements
We thank Bodossaki foundation for valuable support through scholarship to E.T. We thank Zoi Kanaki for extensive technical support with blastocyst microinjections and Apostolos Klinakis for his help with the embryonic stem cells and for valuable discussion. We especially thank Dimitris Vasilatis, Despoina Sanoudou and Stelios Psarras for constant assistance throughout this work.
Funding
The described work, performed by Y.C laboratory, was supported by Greek Secretariat of Research and Development grants (PEP-ATT-39, ESPA SYNERGASIA SYN965, grant of Excellence II/ARISTEIA II 5342) to Y.C.
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E.T. designed and performed experiments, analyzed data, and wrote the manuscript; I.K. performed experiments; I.Kl. performed the electron microscopy experiments; M.T. helped with the design of the gene targeting; D.M. performed behavioral studies; E.V helped with the ES cell experiments; A.V. and C.H.D. performed and analyzed the echocardiography; M.N.B. performed the HPLC experiments; M.M. performed experiments; A.P. designed and performed behavioral studies and wrote the corresponding part of the manuscript; Y.C. directed the research project, designed experimental strategy, analyzed the data, and wrote the manuscript. I.K. and I.Kl. made equal contributions to the work. All authors reviewed and approved the manuscript.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Tsoupri, E., Kostavasili, I., Kloukina, I. et al. Myospryn deficiency leads to impaired cardiac structure and function and schizophrenia-associated symptoms. Cell Tissue Res 385, 675–696 (2021). https://doi.org/10.1007/s00441-021-03447-2
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DOI: https://doi.org/10.1007/s00441-021-03447-2