Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

Abstract

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 help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine

“…For example, a primary biophysical effect of phospholamban mutations—a protein that regulates sarcoplasmic calcium uptake via SERCA2a inhibition—is altered intramyocellular calcium handling; however, the resulting calcium dysregulation will impact both contractility and metabolism due to the increased energetic cost of sequestering calcium. Likewise, altered myofilament contractility due to mutations in cardiac troponin T can affect cellular mechanotransduction ( Clippinger et al, 2019 ), leading to downstream changes in the expression of calcium-handling genes ( Chandra et al, 2001 ; Montgomery et al, 2001 ).…”

Combining Nanomaterials and Developmental Pathways to Design New Treatments for Cardiac Regeneration: The Pulsing Heart of Advanced Therapies

“…In this direction, Hippo pathway has emerged as a possible switch in cardiomyocyte proliferation (Torrini et al, 2019), being tightly connected to the onset and progression of cardiomyopathies (Clippinger et al, 2019), as explained above. Its specific manipulation in the contractile figures of the heart may become a novel therapeutic option for treating cardiac diseases.…”

Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

“…TNNT2 is one of the most frequently mutated genes in DCM [39]. A deletion of lysine 210 (∆K210) in troponin-T causes early-onset DCM [40]. Clippinger et al demonstrated that the ∆K210 mutation shifts the equilibrium positioning of tropomyosin by reducing the number of strongly bound myosin cross-bridges via decreases in the fraction of thin filaments in the open, weakly bound, and strongly bound states and via increases in the fraction of thin filaments in the blocked and close states [40].…”

“…A deletion of lysine 210 (∆K210) in troponin-T causes early-onset DCM [40]. Clippinger et al demonstrated that the ∆K210 mutation shifts the equilibrium positioning of tropomyosin by reducing the number of strongly bound myosin cross-bridges via decreases in the fraction of thin filaments in the open, weakly bound, and strongly bound states and via increases in the fraction of thin filaments in the blocked and close states [40]. They also demonstrated that ∆K210 cardiomyocytes have defects in mechanosensing that may prevent adaptive responses in their contractility and structure in response to changes in the mechanical environment such as disease-related stiffening of cardiac tissue [40].…”