| Title: |
Circulating muscle-derived mir-206 links skeletal muscle dysfunction to cardiac autonomic denervation |
| Authors: |
Zaglia, T.; Prando, V.; Bertoli, S.; Favaro, G.; Di Mauro, V.; Guescini, M.; Di Bona, A.; Lo Verso, F.; Soares, R.; Martins, P. Da Costa; Catalucci, D.; Mongillo, M.; Sandri, M. |
| Source: |
Zaglia, T, Prando, V, Bertoli, S, Favaro, G, Di Mauro, V, Guescini, M, Di Bona, A, Lo Verso, F, Soares, R, Martins, P D C, Catalucci, D, Mongillo, M & Sandri, M 2019, 'Circulating muscle-derived mir-206 links skeletal muscle dysfunction to cardiac autonomic denervation', European Heart Journal, vol. 40, pp. 80-80. https://doi.org/10.1093/eurheartj/ehz747.0078 |
| Publication Year: |
2019 |
| Collection: |
Maastricht University Research Publications |
| Description: |
Purpose Recent studies and our preliminary data demonstrate that muscle-specific ablation of the autophagy-related protein Atg7, leads to block of autophagy, sarcopenia and destabilization of the neuro-muscular junction (NMJ). In addition, Atg7 knock-out (Atg7 KO) muscle fibers release exosomes containing the muscle specific, miR-206, which is consistently elevated in the plasma. Interestingly, we found that miR-206 content was elevated in the heart, suggesting cardiac uptake of the miR-carrying circulating exosomes. We thus aimed at defining the effects of miR-206 on heart homeostasis. Methods Here, we analyzed the cardiac phenotype of adult (12mo.) and aged (24mo.) Atg7 KO mice, as well as of adult C57BL/6J mice injected, via tail vein, with scramble- or miR-206-loaded exosomes. Exosomes were isolated from EDL muscle of control and Atg7 KO mice, as well as from HEK293 cells. Heart function was assessed by echocardiography and ECG-telemetry. Confocal IF, whole-mount IF on heart blocks and multiphoton imaging were used to assess heart structure and sympathetic innervation. Bioinformatics, molecular and biochemical analyses were performed to identify novel targets of miR-206. IF, BRET assay and imaging of TrKA translocation were performed in cultured sympathetic neurons (SNs). Results We demonstrate that circulating exosomes, containing miR-206, are taken up by the heart leading to sympathetic dysinnervation, accompanied to reduction in the neurogenic control of cardiac rhythm and increased arrhythmogenesis. In vitro assays demonstrated that exosome-carried miR-206 targets cardiac SNs (cSNs), compromising cell structure and function. Indeed, increased miR-206 expression is accompanied by cSN atrophy, irregular axonal distribution of the active neurotransmitter release sites, and reduction in axonal sprouting. These effects are likely attributed to the miR-206-mediated down-regulation of the NGF receptor p75, as demonstrated by bioinformatics, luciferase assay, molecular and biochemical analyses in vitro and ex ... |
| Document Type: |
conference object |
| Language: |
English |
| ISSN: |
0195-668X; 1522-9645 |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/000507313000080; info:eu-repo/semantics/altIdentifier/pissn/0195-668X; info:eu-repo/semantics/altIdentifier/eissn/1522-9645 |
| DOI: |
10.1093/eurheartj/ehz747.0078 |
| Availability: |
https://cris.maastrichtuniversity.nl/en/publications/ede21386-9445-4da1-a5df-f092d5fbc51b; https://doi.org/10.1093/eurheartj/ehz747.0078 |
| Rights: |
info:eu-repo/semantics/closedAccess |
| Accession Number: |
edsbas.EA1D7862 |
| Database: |
BASE |