Mapping molecular load in beating heart cells

The heart pumps blood because specialized cells called cardiomyocytes contract and relax. Scientists know that the shape and maturity of these cells affect how strongly they contract, but this insight came from measuring the total force of a whole cell, not how that force is distributed inside it. Dutta et al.’s work opens this black box by revealing the tension on a single protein, α-actinin-2, helping answer a more fundamental question: where is mechanical load carried at the molecular scale?

The study provides direct experimental evidence for the long-held theory that α-actinin-2 bears mechanical load during contraction, with the cardiomyocyte’s overall shape and the protein’s maturity determining whether that tension is actually transmitted across the protein.

“Rectangular cardiomyocytes show a clear increase in tension across α-actinin-2 during contraction. In contrast, circular cells do not show increased tension across this protein,” author Jeroen Eyckmans said. “Early after plating, cells of either shape contract but show little to no tension across α-actinin-2. Only once sarcomeres mature — and only in rectangular cells — do we observe significant loading.”

For the study, the team inserted a genetically encoded, organic tension sensor into α-actinin-2 in.a way that preserved its normal function. The sensor, which was originally developed by author Brenton Hoffman to study other proteins, was then expressed in stem-cell-derived cardiomyocytes grown on rectangular or circular micropatterns. Pairing these experiments with traction force microscopy and a chemo-mechanical model allowed the team to link protein-level tension to molecular organization and whole-cell mechanics.

The authors plan to extend their study to similar proteins in heart muscle, nearly 500 of which have been identified.

Source: “Cell shape and maturation impacts α-actinin-2 tension in iPSC-derived cardiomyocytes,” by Palash K. Dutta, Joshua M. Toth, Subramanian Sundaram, Xingyu Chen, Anant Chopra, Jourdan K. Ewoldt, Paige Cloonan, Xining Gao, Andrew S. LaCroix, Brenton D. Hoffman, Vivek B. Shenoy, Christine E. Seidman, Jonathan G. Seidman, Christopher S. Chen, Jeroen Eyckmans, APL Bioengineering (2026). The article can be accessed at https://doi.org/10.1063/5.0304143 .