Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved..
OBJECTIVES: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy.
BACKGROUND: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear.
METHODS AND RESULTS: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction.
CONCLUSIONS: MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:60 |
|---|---|
| Enthalten in: |
Redox biology - 60(2023) vom: 01. Apr., Seite 102606 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhong, Yuan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Atrial cardiomyopathy |
|---|
| Anmerkungen: |
Date Completed 29.08.2023 Date Revised 13.12.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.redox.2023.102606 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM35156859X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM35156859X | ||
| 003 | DE-627 | ||
| 005 | 20231227131058.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.redox.2023.102606 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1225.xml |
| 035 | |a (DE-627)NLM35156859X | ||
| 035 | |a (NLM)36645977 | ||
| 035 | |a (PII)S2213-2317(23)00007-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhong, Yuan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Myosin light-chain 4 gene-transfer attenuates atrial fibrosis while correcting autophagic flux dysregulation |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.08.2023 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a OBJECTIVES: To determine the role of MYL4 regulation of lysosomal function and its disturbance in fibrotic atrial cardiomyopathy | ||
| 520 | |a BACKGROUND: We have previously demonstrated that the atrial-specific essential light chain protein MYL4 is required for atrial contractile, electrical, and structural integrity. MYL4 mutation/dysfunction leads to atrial fibrosis, standstill, and dysrhythmia. However, the underlying pathogenic mechanisms remain unclear | ||
| 520 | |a METHODS AND RESULTS: Rats subjected to knock-in of a pathogenic MYL4 mutant (p.E11K) developed fibrotic atrial cardiomyopathy. Proteome analysis and single-cell RNA sequencing indicate enrichment of autophagy pathways in mutant-MYL4 atrial dysfunction. Immunofluorescence and electron microscopy revealed undegraded autophagic vesicles accumulated in MYL4p.E11K rat atrium. Next, we identified that dysfunctional MYL4 protein impairs autophagy flux in vitro and in vivo. Cardiac lysosome positioning and mobility were regulated by MYL4 in cardiomyocytes, which affected lysosomal acidification and maturation of lysosomal cathepsins. We then examined the effects of MYL4 overexpression via adenoviral gene-transfer on atrial cardiomyopathy induced by MYL4 mutation: MYL4 protein overexpression attenuated atrial structural remodeling and autophagy dysfunction | ||
| 520 | |a CONCLUSIONS: MYL4 regulates autophagic flux in atrial cardiomyocytes via lysosomal mobility. MYL4 overexpression attenuates MYL4 p.E11K induced fibrotic atrial cardiomyopathy, while correcting autophagy and lysosomal function. These results provide a molecular basis for MYL4-mutant induced fibrotic atrial cardiomyopathy and identify a potential biological-therapy approach for the treatment of atrial fibrosis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Atrial cardiomyopathy | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a Lysosome | |
| 650 | 4 | |a Myosin light chain 4 | |
| 650 | 7 | |a Myosin Light Chains |2 NLM | |
| 650 | 7 | |a Myosins |2 NLM | |
| 650 | 7 | |a EC 3.6.4.1 |2 NLM | |
| 650 | 7 | |a Myl4 protein, rat |2 NLM | |
| 700 | 1 | |a Tang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Nattel, Stanley |e verfasserin |4 aut | |
| 700 | 1 | |a Zhai, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Shiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Yanxi |e verfasserin |4 aut | |
| 700 | 1 | |a E, Guangxi |e verfasserin |4 aut | |
| 700 | 1 | |a Maimaitiaili, Nuerbiyemu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yawei |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Wenhui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hailing |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Redox biology |d 2013 |g 60(2023) vom: 01. Apr., Seite 102606 |w (DE-627)NLM22743725X |x 2213-2317 |7 nnns |
| 773 | 1 | 8 | |g volume:60 |g year:2023 |g day:01 |g month:04 |g pages:102606 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.redox.2023.102606 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 60 |j 2023 |b 01 |c 04 |h 102606 | ||