Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM
Abstract
:1. Introduction
2. Materials and Methods
2.1. Transgenic Mice
2.2. Recombinant RLC Proteins—Cloning, Expression, and Purification
2.3. Mechanical and ATP Turnover Measurements in Skinned Left Ventricular Papillary Muscle (LVPM) Fibers from Transgenic Tg-RLC and Tg-ELC Mice
2.3.1. Preparation of Skinned LVPM Fibers
2.3.2. Depletion of Endogenous RLC from LVPM and Reconstitution with Recombinant RLC Proteins
2.3.3. Steady-State Force Development and Ca2+-Sensitivity of Force in Reconstituted Muscle Strips
2.3.4. Mant-ATP Chase Experiments
2.4. Treatment of Skinned Muscle Strips with Omecamtiv Mecarbil (OM)
2.5. Statistical Analysis
3. Results
3.1. Effect of Phosphomimetic S15D-RLC on Force Measurements in LVPM Fibers from Tg-ELC Mouse Model of RCM
3.2. Effect of Phosphomimetic S15D-RLC on the Super-Relaxed State in LVPM Fibers from Tg-ELC and Tg-RLC Mouse Modes of RCM and DCM
3.2.1. Transgenic ELC Mice
3.2.2. Transgenic RLC Mice
3.3. Treatment of RCM and DCM Mice with Omecamtiv Mecarbil (OM)
3.3.1. Steady-State Force and Force–pCa Relationship
3.3.2. SRX↔DRX Equilibrium in LVPM Fibers from RCM and DCM Mice
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Force Parameter/ Recombinant RLC-Reconstituted LVPM | LVPM from Tg-WT ELC Mice | LVPM from Tg-E143K Mice | ||
---|---|---|---|---|
WT | S15D | WT | S15D | |
N° fibers | 8 | 7 | 9 | 10 |
Fmax (kN/m2) ± SD | 21.56 ± 4.64 | 34.25 ± 9.66 ** | 23.56 ± 4.42 | 28.58 ± 1.95 |
pCa50 ± SD | 5.32 ± 0.1 | 5.41 ± 0.06 * | 5.51 ± 0.09 | 5.51 ± 0.09 |
nH ± SD | 2.03 ± 0.74 | 1.87 ± 0.41 | 2.2 ± 0.61 | 1.73 ± 0.24 * |
SRX Parameter/Recombinant RLC-Reconstituted LVPM | LVPM from Tg-WT ELC Mice | LVPM from Tg-E143K ELC Mice | ||||
---|---|---|---|---|---|---|
Native | WT | S15D | Native | WT | S15D | |
N° fibers | 14 | 6 | 7 | 13 | 11 | 10 |
DRX (%) ± SD | 38.9 ± 8.2 | 35.1 ± 14.2 | 37.2 ± 18.8 | 29.4 ± 3.7 ## | 32.3 ± 11.9 | 44 ± 12.8 * |
SRX (%) ± SD | 61.1 ± 8.2 | 64.9 ± 14.2 | 62.8 ± 18.8 | 70.6 ± 3.7 ## | 67.8 ± 11.9 | 56 ± 12.8 * |
T1 (s) ± SD | 4.4 ± 2.4 | 6.6 ± 4.9 | 5.3 ± 2.5 | 4.2 ± 2.5 | 4.8 ± 3.6 | 7 ± 5.2 |
T2 (s) ± SD | 129.8 ± 67 | 125.3 ± 81.3 | 173.4 ± 167.7 | 126.5 ± 81.2 | 92.2 ± 64 | 136.4 ± 116.5 |
SRX Parameter/Recombinant RLC-Reconstituted LVPM | LVPM from Tg-D94A RLC Mice | |||
---|---|---|---|---|
Native | WT | S15D | D94A | |
No. fibers | 13 | 13 | 8 | 12 |
DRX ± SD | 26.3 ± 7.3 | 44.9 ± 10.2 ****,^ | 46.7 ± 13.2 ****,^ | 33.6 ± 6.4 |
SRX ± SD | 73.7 ± 7.3 | 55.1 ± 10.2 ****,^ | 53.3 ± 13.2 ****,^ | 66.4 ± 6.4 |
T1 ± SD | 6.5 ± 3.3 | 4.9 ± 2.8 | 5.7 ± 5.1 | 2.7 ± 1.7 * |
T2 ± SD | 161.8 ± 149 | 136.9 ± 103.1 | 117.7 ± 130.8 | 67.4 ± 77.3 |
Force Parameter/ OM- vs. Placebo-Treated Fibers | LVPM from Tg-WT ELC Mice | LVPM from Tg-E143K ELC Mice | LVPM from Tg-WT RLC Mice | LVPM from Tg-D94A RLC Mice | ||||
---|---|---|---|---|---|---|---|---|
OM | Placebo | OM | Placebo | OM | Placebo | OM | Placebo | |
No. fibers | 6 | 4 | 6 | 4 | 8 | 4 | 6 | 4 |
Fmax (kN/m2) ± SD | 66.4 ± 5.1 *** | 48.3 ± 4.5 | 56.8 ± 4.8 * | 47.8 ± 3.2 | 55.8 ± 5.7 | 51.7 ± 2 | 64.5 ± 7.8 ** | 46.9 ± 8.1 |
pCa50 ± SD | 5.9 ± 0.1 ** | 5.5 ± 0.04 | 5.7 ± 0.1 | 5.6 ± 0.03 | 5.9 ± 0.1 *** | 5.6 ± 0.1 | 5.8 ± 0.1 * | 5.6 ± 0.1 |
nH ± SD | 1.2 ± 0.1 * | 1.5 ± 0.2 | 1.8 ± 0.2 * | 2.2 ± 0.1 | 1.5 ± 0.2 ** | 2 ± 0.2 | 1.9 ± 0.3 * | 2.2 ± 0.2 |
SRX Parameter/ OM- vs. Placebo-Treated Fibers | LVPM from Tg-WT ELC Mice | LVPM from Tg-E143K ELC Mice | LVPM from Tg-WT RLC Mice | LVPM from Tg-D94A RLC Mice | ||||
---|---|---|---|---|---|---|---|---|
OM | Placebo | OM | Placebo | OM | Placebo | OM | Placebo | |
No. fibers | 14 | 13 | 10 | 12 | 12 | 14 | 11 | 12 |
DRX ± SD | 41.6 ± 10.4 | 40.1 ± 8.5 | 41.1 ± 10.3 ** | 28.8 ± 6.7 | 39.3 ± 13.4 | 35.9 ± 8.5 | 47.2 ± 15.3 **** | 22.7 ± 6.2 |
SRX ± SD | 58.4 ± 10.4 | 59.9 ± 8.5 | 58.9 ± 10.3 ** | 71.2 ± 6.7 | 60.7 ± 13.4 | 64.1 ± 8.5 | 52.8 ± 15.3 **** | 77.3 ± 6.2 |
T1 ± SD | 3.7 ± 3.4 | 3.2 ± 1.8 | 3.7 ± 2.4 | 4.2 ± 2.7 | 4.2 ± 3 | 5.6 ± 3.8 | 3.7 ± 1.9 * | 6.9 ± 4.1 |
T2 ± SD | 101.4 ± 152.5 | 69 ± 38.5 | 89.3 ± 78.9 | 112.9 ± 94.3 | 123.8 ± 86.8 | 119.6 ± 122.4 | 83.1 ± 65.6 * | 230.6 ± 213.8 |
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Kazmierczak, K.; Liang, J.; Maura, L.G.; Scott, N.K.; Szczesna-Cordary, D. Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM. Life 2023, 13, 1463. https://doi.org/10.3390/life13071463
Kazmierczak K, Liang J, Maura LG, Scott NK, Szczesna-Cordary D. Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM. Life. 2023; 13(7):1463. https://doi.org/10.3390/life13071463
Chicago/Turabian StyleKazmierczak, Katarzyna, Jingsheng Liang, Luis G. Maura, Natissa K. Scott, and Danuta Szczesna-Cordary. 2023. "Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM" Life 13, no. 7: 1463. https://doi.org/10.3390/life13071463