Research Article

New insights from cardiac muscle applied to skeletal muscle

Gerry A Smith*

Published: 01/15/2021 | Volume 6 - Issue 1 | Pages: 007-013

I have recently described the origin of the second Ca2+ binding in the triggering of contractile activity in cardiac myofibrils that is the origin of the Ca2+ Hill coefficient of 2 for the ATPase. This site is not a simple protein binding site and cannot be measured by 45Ca2+ binding. The myofibril protein unit requirements are described by me and so are the consequences of disruption of the function of these units and the related medical outcomes. The purpose of this paper is to review the topic and extend the reasoning to the function of skeletal muscle and cite the literature that supports this.

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  1. Smith GA, Vandenberg JI, Freestone NS, Dixon HBF. The effect of Mg2+ on cardiac muscle function: Is CaATP the substrate for priming myofibril cross-bridge formation and Ca2+ reuptake by the sarcoplasmic reticulum? Biochem J. 2001; 354: 539-551. PubMed:
  2. Smith GA. Calcium, actomyosin kinetics, myosin binding protein-c and hypertrophic cardiomyopathy. J Integr Cardiol. 2019; 5: 1-2.
  3. Smith GA. The Mechanisms of the Frank-Starling Law and Familial Cardiomyopathy are Different. The Function of Myosin Binding Protein-C is Retained on Myocyte Length Increase and Force Generated is Kinase controlled. J Integr Cardiol. 2019; 5: 1-3.
  4. Smith GA. Angiotensin II type 1 receptor and the activation of Myosin Light-Chain Kinase and Protein Kinase C-βII: Mini Review. J Cardiol Cardiovasc Med. 2020; 5: 024-028.
  5. Smith GA. The Mechanisms of Cardiac Myopathies, a kinetics approach. Leading review. J Cardiol Cardiovasc Med. 2020; 5: 141-152.
  6. Brandt PW, Diamond MS, Gluck B, Kawai M, Schachat F. Molecular Basis of Cooperativity in Vertebrate Muscle Thin Filaments Carlsberg Res. Commun. 1984; 49: 155-167.
  7. Hofmann PA, Hartzell HC, Moss RL. Alterations in Ca2+ sensitive tension due to partial extraction of C-protein from rat skinned cardiac myocytes and rabbit skeletal muscle fibers. J Gen Physiol. 1991; 97: 1141-1163. PubMed:
  8. Katrukha IA. Human Cardiac Troponin Complex. Structure and Functions. Biochemistry (Moscow). 2013; 78: 1447-14650. PubMed:
  9. Layland J, Solaro RJ, Shah AM. Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovascular Res. 2005; 66: 12–21. PubMed:
  10. Westfall MV, Lee AM, Robinson DA. Differential Contribution of Troponin I Phosphorylation Sites to the Endothelin-modulated Contractile Response. J Biol Chem. 2005; 280: 41324–41331. PubMed:
  11. Sheng JJ, Jin JP. TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure–function relationships. Gene. 2016; 576: 385-394. PubMed:
  12. Robinson P, Lipscomb S, Preston LC, Altin E, Watkins H, et al. Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function. FASEB J. 2007; 21: 896–905. PubMed:  
  13. Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001; 104: 557–567. PubMed:
  14. Curila K, Benesova L, Penicka M, Minarik M, Zemanek D, et al. Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy. Acta Cardiol. 2012; 67: 23–29. PubMed:
  15. Heling LWHJ, Geeves MA, Kad NM. MyBP-C: one protein to govern them all. J. Muscle Res. and Cell Motility. 2020; 41: 91–101.
  16. Lin B, Govindan S, Lee K, Zhao P, Renzhi Han R, et al. Cardiac Myosin Binding Protein-C Plays No Regulatory Role in Skeletal Muscle Structure and Function. PLoS One. 2013; 8: e69671. PubMed:
  17. Lee RS. Effect of the Ca2+ Binding Properties of Troponin C On Skeletal and Cardiac Muscle Force Development. Thesis the Ohio State University. 2010.
  18. Potter JD, Gergely J. J Biol Chem. 1975; 250: 4628-4633.
  19. Kretsinger RH. CRC Crit Rev Biochem. 1980; 8: 119-174.
  20. Sia SK, Li MX, Spyracopoulos L, Gagne SM, Liu W, et al. J Biol Chem. 1997; 272: 18216-18221.
  21. Brandt PW, Cox RN, Kawai M. Can the binding of Ca2+ to two regulatory sites on troponin-C determine the steep pCa/tension relationship of skeletal muscle? Proc Natl Acad Sci. 1980; 77: 4717-4720. PubMed:
  22. Kampourakis T, Yan Z, Gautel M, Sun YB, Irving M. Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells PNAS. 2014; 111: 18763–18768. PubMed:
  23. Flashman E, Watkins H, Redwood C. Localization of the binding site of the C-terminal domain of cardiac myosin-binding protein-C on the myosin rod. Biochem J. 2007; 401: 97–102. PubMed:
  24. van Dijk SJ. Bezold KL, Harris SP. Earning Stripes: Myosin Binding Protein-C Interactions with Actin. Pflugers Arch. 2014; 466: 445–450. PubMed:
  25. Lu Y, Kwan AH, Trewhella J, Jeffries CM. Communication: The C0C1 Fragment of Human Cardiac Myosin Binding Protein C Has Common Binding Determinants for Both Actin and Myosin. J Mol Biol. 2011; 413: 908–913. PubMed:
  26. Moss RL, Giulian GG, Greaser ML. The effects of partial extraction of TnC upon the tension-pCa relationship in rabbit skinned skeletal muscle fibers. J Gen Physiol. 1985; 86: 585–600. PubMed:
  27. Morimoto S, Ohtsuki I. Role of Troponin C in Determining the Ca2+ -Sensitivity and Cooperativity of the Tension Development in Rabbit Skeletal and Cardiac Muscles. J Biochem. 1994; 115: 144-146.
  28. Zot HG, Potter JD. A structural role for the Ca2+-Mg2+ sites on troponin C in the regulation of muscle contraction. Preparation and properties of troponin C depleted myofibrils. J Biol Chem. 1982; 257: 7678-7683. PubMed:
  29. Pohlmann L, Kröger I, Vignier N, Schlossarek S, Krämer E, et al. Cardiac Myosin-Binding Protein C Is Required for Complete Relaxation in Intact Myocytes. Circ Res. 2007; 101: 928-938.         PubMed:
  30. Lecarpentier Y, Vignier N, Oliviero P, Guellich A, Carrier L, et al. Cardiac Myosin-Binding Protein C Modulates the Tuning of the Molecular Motor in the Heart. Biophysical J. 2008; 95: 720–728. PubMed:
  31. Razumova MV, Bezold KL, Tu AY, Regnier M, Harris SP. Contribution of the Myosin Binding Protein C Motif to Functional Effects in Permeabilized Rat Trabeculae. J Gen Physiol. 2008; 132: 575–585. PubMed:
  32. Lin BL, Li A, Mun JY, Previs MJ, Previs SB, et al. Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner. Nature, Scientific Reports. 2018; 8: 2604. PubMed:
  33. Oakley CE, Chamoun J, Brown LJ, Hamblya BD. Binding protein-C: Enigmatic regulator of cardiac contraction. Int J Biochem Cell Biol. 2007; 39: 2161–2166. PubMed:
  34. Orlova A, Galkin VE, Cy MJ, Jeffries Cy MJ, Egelman EH, et al. The N-terminal Domains of Myosin Binding Protein C Can Bind Polymorphically to F-Actin. J Mol Biol. 2011; 412: 379–386.PubMed:
  35. Li A. Nelson SR, Rahmanseresht S, Braet F, Cornachione AS, et al. Skeletal MyBP-C isoforms tune the molecular contractility of divergent skeletal muscle systems. PNAS. 2019; 116: 21882–21892. PubMed:  
  36. Chen Z, Zhao TJ, Li J, Gao YS, Meng FG, et al. Slow skeletal muscle myosin-binding protein-C (MyBPC1) mediates recruitment of muscle-type creatine kinase (CK) to myosin. Biochem J. 2011; 436: 437-445. PubMed: