Active sensing of the environment

To form the proper architecture of the heart, the cells need to sense their local environment, both the neighboring cells and the local matrix fibers. When cells die or fibers are altered, the remaining cells need to either activate repair processes or adapt to the altered conditions. In studies of fibroblasts and epithelial cells, active mechanosensing systems have been described that sense matrix rigidity (Wolfenson et al. 2016) and the rigidity of neighboring cells (Yang et al. 2018). In the case of matrix rigidity sensors, fibroblasts will assemble sarcomeric units that bridge new matrix bind sites separated by 1–3 μm and will contract to a constant length of ~100nm and relax over 30–60s (Fig. 1). At the peak of contraction, the tension in the sensor will be proportional to matrix rigidity. In fibroblasts, the rigidity sensor will activate growth on rigid matrices but will activate apoptosis on soft (Wolfenson et al. 2016; Yang et al. 2020). Similar active mechanosensors are likely to test the tension of cardiac collagen fibers and activate biomechanical processes to maintain the desired fiber tension (Pandey et al. 2018). It should be noted that these active sensors make only occasional and transient measurements of the mechanical aspects of the environment. The signals generated by the sensors are also transient but often have long-term consequences for the cell. Thus, mechanobiological processes are continuously involved in the maintenance of the proper mechanical properties of the tissue, whether it be the vasculature, the heart, or the other organs. Often changes in activity levels by individuals will be reflected in changes in organ function but those changes can take weeks to months to be fully implemented. This makes it very hard to understand the molecular-level processes that underlie those changes.

Fig. 1
figure 1

Diagrams of active rigidity sensors for A matrix rigidity (Wolfenson et al. 2019) and for B cadherin rigidity (Yang et al. 2018). In both cases, the sarcomeres contract briefly (30–60s) to a constant displacement of about 100 nm and the maximum force of contraction is proportional to the rigidity. Many downstream signaling pathways are linked to the sensors

Mechanical therapies

As it becomes clearer that mechanical activity can alter organ function through changes in cell behavior, it will become possible to use mechanical treatments to correct some undesirable behaviors. For example, we have found that ultrasound will cause apoptosis of many different tumor cells (Tijore et al. 2020), and since the ultrasound can penetrate the body, this affords the possibility of non-invasive treatment of many cancers. Exercise is a clearly beneficial mechanical therapy that may be further optimized for the organ of interest and can be combined with biochemical therapies to improve the desired outcome. There can be many benefits from the targeted use of mechanical activities to counteract certain cell behaviors and enhance others. Mechanobiology has the promise of providing many benefits to health from the non-invasive use of mechanical activity to modify cell function.

Where to from here

As it becomes clearer that mechanical activity provides therapeutic value to the tissue and the organism, there will be an increase in molecular studies to provide a greater understanding of the molecular processes involved in transduction of stresses and strains into biochemical changes, e.g., the mechanism of stretch-induced apoptosis of tumor cells (Tijore et al. 2021). Since multiple mechanical therapies, exercise (Chen et al. 2021), stretching-massage (Zhang et al. 2019), ultrasound (Tijore et al. 2020), and potentially others, can act through similar pathways, it should be possible to design treatments for a variety of disorders that are tailored to the patient. The goal is to increase the functional activities of cells that will enable rejuvenation, repair, and regeneration without the need to resort to drugs but rather to exploit the mechanical pathways that are behind the old adage of “use it or lose it.”