Lab News

The Greenberg lab went to Ted Drewes to celebrate the publication of our Biophysical Journal paper.

https://www.ncbi.nlm.nih.gov/pubmed/31126584

Congratulations to Sami Pathak on receiving a BioSURF fellowship for his studies on regulation of the troponin complex.

Sarah Clippinger had a talk and Sam Barrick presented a poster at the Biophysical Society Annual Meeting in Baltimore.

https://www.biorxiv.org/content/10.1101/555391v1

Sarah R Clippinger, Paige E Cloonan, Lina Greenberg, Melanie Ernst, W. Tom Stump, Michael J Greenberg

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

https://www.biorxiv.org/content/10.1101/548404v3

Samantha K Barrick, Sarah R Clippinger, Lina Greenberg, Michael J Greenberg

Striated muscle contraction occurs when myosin thick filaments bind to thin filaments in the sarcomere and generate pulling forces. This process is regulated by calcium, and it can be perturbed by pathological conditions (e.g., myopathies), physiological adaptations (e.g., β-adrenergic stimulation), and pharmacological interventions. Therefore, it is important to have a methodology to robustly determine the mechanism of these perturbations and statistically evaluate their effects. Here, we present an approach to measure the equilibrium constants that govern muscle activation, estimate uncertainty in these parameters, and statistically test the effects of perturbations. We provide a MATLAB-based computational tool for these analyses, along with easy-to-follow tutorials that make this approach accessible. The hypothesis testing and error estimation approaches described here are broadly applicable, and the provided tools work with other types of data, including cellular measurements. To demonstrate the utility of the approach, we apply it to determine the biophysical mechanism of a mutation that causes familial hypertrophic cardiomyopathy. This approach is generally useful for studying the mechanisms of muscle diseases and therapeutic interventions that target muscle contraction.

https://www.ncbi.nlm.nih.gov/pubmed/30744991

Michael presented the lab’s work at Duke for the Computational Biology and Bioinformatics program.