Contractile Properties of Striated Muscle in Development and In Disease
Racca, Alice Ward
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In utero development is a key time for muscle formation, and muscle-related birth defects are sometimes linked to mutations in muscle contractile proteins expressed in utero. Even in heart disease, the development of the disease pre-dates the clinical symptoms; however, studying the developing muscle before it presents in clinic is difficult. Muscle contractility can be studied directly, and the use of multiple assays has allowed me to examine muscle development and disease at the protein, subcellular, and cellular level. Distal arthrogryposis is a skeletal muscle birth defect that can be caused by a mutation in embryonic myosin; herein, I have found that the continued muscle dysfunction is linked to a delay in relaxation, likely from slower cross-bridge detachment, and that this is not from an overexpression of embryonic myosin. Fetal muscle in which embryonic myosin is highly expressed is slow to activate and relax, and generates very little force, even compared to fetal cardiac muscle of a similar age. Fetal cardiac muscle develops more force as gestation increase, showing an increase in activation and relaxation rates, though the cross-bridge cycling rates appear to fluctuate, potentially as a function of structure. The fetal cardiac muscle is a good milestone for assessing the maturity of human induced pluripotent stem cell derived cardiomyocytes, which are used to model heart disease and therapeutics, and produce force at rates of activation and relaxation that are close to those of fetal cardiac myofibrils and not adult cardiac myofibrils. The human induced pluripotent stem cell derived cardiomyocytes from patients with known mutations show potentially early onset factors in cardiomyopathy. Finally, failing adult cardiac muscle demonstrates that the activation rate and force production of the myofilament can be enhanced without slowing the relaxation through using 2-deoxy-ATP.
- Bioengineering