Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions
Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 8 vom: 20. Feb., Seite e2314914121 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ma, Weikang [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
56HH86ZVCT |
|---|
| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 28.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Aug 28;:. - PMID 37090664 Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.2314914121 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368363406 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368363406 | ||
| 003 | DE-627 | ||
| 005 | 20240229170949.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240213s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.2314914121 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1310.xml |
| 035 | |a (DE-627)NLM368363406 | ||
| 035 | |a (NLM)38346202 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ma, Weikang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions |
| 264 | 1 | |c 2024 | |
| 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 14.02.2024 | ||
| 500 | |a Date Revised 28.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Aug 28;:. - PMID 37090664 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a cardiac reserve | |
| 650 | 4 | |a mavacamten | |
| 650 | 4 | |a myosin | |
| 650 | 4 | |a thick filament | |
| 650 | 7 | |a MYK-461 |2 NLM | |
| 650 | 7 | |a Myosins |2 NLM | |
| 650 | 7 | |a EC 3.6.4.1 |2 NLM | |
| 650 | 7 | |a Benzylamines |2 NLM | |
| 650 | 7 | |a Uracil |2 NLM | |
| 650 | 7 | |a 56HH86ZVCT |2 NLM | |
| 700 | 1 | |a Del Rio, Carlos L |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Prodanovic, Momcilo |e verfasserin |4 aut | |
| 700 | 1 | |a Mijailovich, Srboljub |e verfasserin |4 aut | |
| 700 | 1 | |a Zambataro, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Henry |e verfasserin |4 aut | |
| 700 | 1 | |a Shimkunas, Rafael |e verfasserin |4 aut | |
| 700 | 1 | |a Gollapudi, Sampath |e verfasserin |4 aut | |
| 700 | 1 | |a Nag, Suman |e verfasserin |4 aut | |
| 700 | 1 | |a Irving, Thomas C |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 121(2024), 8 vom: 20. Feb., Seite e2314914121 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:121 |g year:2024 |g number:8 |g day:20 |g month:02 |g pages:e2314914121 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2314914121 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 121 |j 2024 |e 8 |b 20 |c 02 |h e2314914121 | ||