Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Genetic Basis of Heart Disease

Background:

• Heritable cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), present diverse clinical outcomes despite shared genetic origins.
• The molecular mechanisms underlying phenotypic divergence from mutations in the same sarcomeric protein, such as TPM1, are not fully understood.

Purpose of the Study:

• To elucidate the mechanistic basis for divergent phenotypes in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) caused by distinct TPM1 mutations (E62Q and E54K).

Main Methods:

• Utilized literature data and experiments with stem cell-derived cardiomyocytes expressing TPM1 mutations.
• Constructed computational simulations to model muscle contractility alterations.
• Investigated gene expression changes in human engineered heart tissues.
• Employed modulators of myosin activity to validate proposed mechanisms.

Main Results:

• The E62Q mutation (HCM) was linked to increased calcium sensitivity and hypercontractility, explained by reduced tropomyosin stiffness and altered actin interactions favoring a 'closed' regulatory state.
• The E54K mutation (DCM) appeared to induce long-range allosteric effects, increasing the association rate of the troponin I mobile domain to tropomyosin/actin.
• These distinct molecular events correlated with observable differences in gene expression in engineered heart tissues.

Conclusions:

• TPM1 mutations E62Q and E54K result in divergent cardiomyocyte phenotypes through distinct molecular mechanisms affecting calcium sensitivity, actin-tropomyosin interactions, and allosteric regulation.
• Computational modeling and experimental validation provide a mechanistic framework for understanding how mutations in the same gene can lead to opposing heart disease phenotypes.
• These findings offer insights into targeted therapeutic strategies for inherited cardiomyopathies.