Investigating the sarcolemma-sarcomere connection and force transmission in the heart

External mechanical signals are communicated through cardiac muscle cells by converting them to internal biochemical signals during mechanotransduction. In the heart, altered transmission of these signals can affect myocardial structure and function. This study examines the impact of sarcospan deletion, a sarcolemma protein, on cardiac muscle mechanics. Sarcospan is an integral member of the dystrophin-glycoprotein complex (DGC) and we are interested in investigating how it influences sarcomere contractile function. Measurements of cardiac contractile parameters were conducted using permeabilized left ventricular papillary muscle bundles obtained from wild-type and SSPN-deficient (SSPN-/-) mouse hearts. Myofilament Ca2+-sensitivity and cooperativity of thin filament activation was similar between WT and SSPN-/- cardiac muscle preparations. However, SSPN-/- muscle bundles exhibited a significantly faster rate of tension redevelopment (kTR) at submaximal activation conditions (pCa 5.8) but no significant changes in maximal kTR (recorded at maximal Ca2+ activation, pCa 4.5). Maximal steady-state isometric force and sinusoidal stiffness were proportionally increased in SSPN-/- cardiac muscle preparations during Ca2+ activation. These intriguing observations suggest that SSPN may play an inherent role in balancing pathways involved in force transmission and its deletion may cause compensatory remodeling of sarcomeric proteins (e.g. isoform switching or protein modification) changing mechanical properties of cardiac muscle. Mouse hearts lacking SSPN-/- exhibit increased sarcolemmal expression of integrin-linked kinase (ILK) and vinculin. ILK is an important biomechanical sensor shown to regulate cardiac contractility and ventricular hypertrophy whereas increasing vinculin expression has been shown to improve heart function and impact myofilament organization. Further examination of the WT and SSPN-/- myofibrils will allow us to assess sarcomere protein alterations that contribute to increased force at submax and max levels of Ca2+ activation. Therefore, the concentric enlargement observed in SSPN-/- mouse hearts could be explained by remodeling of the sarcomere itself.