Skeletal MyBP-C isoforms tune the molecular contractility of divergent skeletal muscle systems
Skeletal muscle myosin-binding protein C (MyBP-C) is a myosin thick filament-associated protein, localized through its C terminus to distinct regions (C-zones) of the sarcomere. MyBP-C modulates muscle contractility, presumably through its N terminus extending from the thick filament and interacting with either the myosin head region and/or the actin thin filament. Two isoforms of MyBP-C (fast- and slow-type) are expressed in a muscle type-specific manner. Are the expression, localization, and Ca2+-dependent modulatory capacities of these isoforms different in fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles derived from Sprague-Dawley rats? By mass spectrometry, 4 MyBP-C isoforms (1 fast-type MyBP-C and 3 N-terminally spliced slow-type MyBP-C) were expressed in EDL, but only the 3 slow-type MyBP-C isoforms in SOL. Using EDL and SOL native thick filaments in which the MyBP-C stoichiometry and localization are preserved, native thin filament sliding over these thick filaments showed that, only in the C-zone, MyBP-C Ca2+ sensitizes the thin filament and slows thin filament velocity. These modulatory properties depended on MyBP-C's N terminus as N-terminal proteolysis attenuated MyBP-C's functional capacities. To determine each MyBP-C isoform's contribution to thin filament Ca2+ sensitization and slowing in the C-zone, we used a combination of in vitro motility assays using expressed recombinant N-terminal fragments and in silico mechanistic modeling. Our results suggest that each skeletal MyBP-C isoform's N terminus is functionally distinct and has modulatory capacities that depend on the muscle type in which they are expressed, providing the potential for molecular tuning of skeletal muscle performance through differential MyBP-C expression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 43 vom: 22. Okt., Seite 21882-21892 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Amy [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.04.2020 Date Revised 07.04.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1910549116 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301983232 |
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| 100 | 1 | |a Li, Amy |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Skeletal MyBP-C isoforms tune the molecular contractility of divergent skeletal muscle systems |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Skeletal muscle myosin-binding protein C (MyBP-C) is a myosin thick filament-associated protein, localized through its C terminus to distinct regions (C-zones) of the sarcomere. MyBP-C modulates muscle contractility, presumably through its N terminus extending from the thick filament and interacting with either the myosin head region and/or the actin thin filament. Two isoforms of MyBP-C (fast- and slow-type) are expressed in a muscle type-specific manner. Are the expression, localization, and Ca2+-dependent modulatory capacities of these isoforms different in fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles derived from Sprague-Dawley rats? By mass spectrometry, 4 MyBP-C isoforms (1 fast-type MyBP-C and 3 N-terminally spliced slow-type MyBP-C) were expressed in EDL, but only the 3 slow-type MyBP-C isoforms in SOL. Using EDL and SOL native thick filaments in which the MyBP-C stoichiometry and localization are preserved, native thin filament sliding over these thick filaments showed that, only in the C-zone, MyBP-C Ca2+ sensitizes the thin filament and slows thin filament velocity. These modulatory properties depended on MyBP-C's N terminus as N-terminal proteolysis attenuated MyBP-C's functional capacities. To determine each MyBP-C isoform's contribution to thin filament Ca2+ sensitization and slowing in the C-zone, we used a combination of in vitro motility assays using expressed recombinant N-terminal fragments and in silico mechanistic modeling. Our results suggest that each skeletal MyBP-C isoform's N terminus is functionally distinct and has modulatory capacities that depend on the muscle type in which they are expressed, providing the potential for molecular tuning of skeletal muscle performance through differential MyBP-C expression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a calcium regulation | |
| 650 | 4 | |a in vitro motility | |
| 650 | 4 | |a mass spectrometry | |
| 650 | 4 | |a muscle contraction | |
| 650 | 4 | |a myosin thick filament | |
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| 650 | 7 | |a Protein Isoforms |2 NLM | |
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| 700 | 1 | |a Nelson, Shane R |e verfasserin |4 aut | |
| 700 | 1 | |a Rahmanseresht, Sheema |e verfasserin |4 aut | |
| 700 | 1 | |a Braet, Filip |e verfasserin |4 aut | |
| 700 | 1 | |a Cornachione, Anabelle S |e verfasserin |4 aut | |
| 700 | 1 | |a Previs, Samantha Beck |e verfasserin |4 aut | |
| 700 | 1 | |a O'Leary, Thomas S |e verfasserin |4 aut | |
| 700 | 1 | |a McNamara, James W |e verfasserin |4 aut | |
| 700 | 1 | |a Rassier, Dilson E |e verfasserin |4 aut | |
| 700 | 1 | |a Sadayappan, Sakthivel |e verfasserin |4 aut | |
| 700 | 1 | |a Previs, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Warshaw, David M |e verfasserin |4 aut | |
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