BPS2026 – Mechanisms of mechanosensing by MLP and α-actinin-2 in cardiac hypertrophy

The cardiac Z-disc is a mechanotransduction hub that links sarcomeric forces to hypertrophic signaling in cardiomyocytes (CMs), yet the underlying mechanisms that link mechanical forces to the activation of intracellular signaling remain poorly understood. We hypothesize that muscle LIM protein (MLP/CSRP3) and α-actinin-2 form a mechanosensory complex that couples sarcomeric load to the activation of signaling pathways that drive CM hypertrophy in health and disease. Using single-molecule biophysical assays, human iPSC-derived CMs, and live-cell imaging, we examine how force alters the stability and dynamics of the MLP/α-actinin-2/F-actin complex and how mechanosensing by this complex drives the translocation of MLP from Z-discs to the nucleus, where it promotes pro-hypertrophic transcriptional programs. In parallel, we examine how mechanosensing by MLP and α-actinin-2 regulates calcineurin signaling, a central regulator of CM hypertrophy. Together, these studies help to elucidate how the Z-disc converts mechanical load into intracellular signaling that governs CM hypertrophy.