Muscle organisation in a diseased heart. Image credit: Leonardo Sacconi (CC BY 4.0)
Muscles enable our bodies to move and our hearts to beat by converting chemical energy into mechanical force. This process depends on proteins within muscle cells, including myosin, a molecular motor that generates force by interacting with actin.
Myosin can adopt different structural states, allowing it to generate force when needed while remaining inactive when contraction is not required. In relaxed muscle, some myosin motors remain available to interact with actin and generate force, while others adopt inhibited configurations that prevent unnecessary interactions and conserve energy.
Efficient switching between these states is essential for normal muscle function. Disrupting this balance can contribute to diseases such as hypertrophic cardiomyopathy, in which the heart muscle becomes abnormally thickened and pumps blood less efficiently. However, directly measuring distinct myosin states remains challenging. New approaches to detect these states could improve our understanding of muscle disease and the effects of drugs that target myosin.
Arecchi et al. wanted to determine whether a specialised microscopy technique could detect differences in the balance between relaxed myosin states in muscle samples and reveal changes caused by disease-associated mutations or drugs. The researchers focused on hypertrophic cardiomyopathy because mutations in myosin are a common cause of the condition. However, measuring myosin states could also be useful for studying other muscle disorders and testing treatments that alter myosin function.
Arecchi et al. used polarised second harmonic generation microscopy, an optical imaging technique sensitive to the orientation of myosin molecules, to study muscle samples from rabbits, mice and genetically modified minipigs carrying a hypertrophic cardiomyopathy-associated myosin mutation. They found that the technique could detect changes in relaxed myosin states caused by both the disease-associated mutation and mavacamten, a drug used to treat hypertrophic cardiomyopathy that reduces myosin activity. The mutation increased the proportion of myosin able to enter a force-generating state, whereas mavacamten promoted a more inhibited state. These findings establish polarised second harmonic generation microscopy as a tool for investigating myosin regulation and evaluating treatments that target muscle contraction.
The work of Arecchi et al. provides a new way to study how myosin changes in health and disease and to investigate drugs that modify muscle contraction. In the future, the approach could help improve understanding of hypertrophic cardiomyopathy and other muscle disorders and support the development and evaluation of new treatments. Further studies will be needed to determine how widely the technique can be applied across different diseases and experimental settings.
