We use a combination of human, animal and stem cell models to study how disease causing mutations affect the properties of the contractile organelles of muscle cells – myofibrils. Multi-scale analysis is used to determine how mutations can result in altered structure and composition of sarcomeres, organization of myofibril packing and the shape of myocytes and tissue. A main goal of this research is to determine how changes at the nano-meter and millisecond scales of contractile proteins manifest into dysfunction at the higher order scales of muscle. These multi-scale approaches also provide testing platforms for developing novel therapeutic approaches and information about best cellular targets for therapeutic development.
Related Publications
- Davis J, Davis LC, Correll RN, Makarewich CA, Schwanekamp JA, Moussavi-Harami F, Wang D, York AJ, Wu H, Houser SR, Seidman CE, Seidman JG, Regnier M, Metzger JM, Wu JC, Molkentin JD. A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy. Cell. 2016 May 19;165(5):1147-59. PubMed PMID: 27114035; PubMed Central PMCID: PMC4874838.
- Cheng Y, Lindert S, Kekenes-Huskey P, Rao VS, Solaro RJ, Rosevear PR, Amaro R, McCulloch AD, McCammon JA, Regnier M. Computational studies of the effect of the S23D/S24D troponin I mutation on cardiac troponin structural dynamics. Biophys J. 2014 Oct 7;107(7):1675-85. PubMed PMID: 25296321; PubMed Central PMCID: PMC4190606.
- Racca AW, Beck AE, McMillin MJ, Korte FS, Bamshad MJ, Regnier M. The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. Hum Mol Genet. 2015 Jun 15;24(12):3348-58. PubMed PMID: 25740846; PubMed Central PMCID: PMC4481580.
- Cheng Y, Rao V, Tu AY, Lindert S, Wang D, Oxenford L, McCulloch AD, McCammon JA, Regnier M. Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation. J Biol Chem. 2015 Nov 13;290(46):27749-66. PubMed PMID: 26391394; PubMed Central PMCID: PMC4646022.