Despite the extensive volume occupied by myofilaments in cardiomyocytes, a direct modulatory role by calmodulin (CaM) has never been described. Our preliminary findings suggested that CaM shifted myosin from dormant states to DRX, prolonged myosin attachment, and enhanced myofilament force generation of left ventricular (LV) cardiac muscle. To further explore if this enhancement was mediated by myosin isoform, pig demembranated cardiac muscle bundles (CMBs) from left atria (LA) were incubated with 2 μM CaM. Ultrastructural changes were assessed using small angle X-ray fiber diffraction in relaxed CMBs; and filament sliding assays were employed with atrial and ventricular myosin. CMBs from LA incubated with CaM showed significant decreases in steady-state isometric forces at physiological levels of activation and beyond. CaM-incubated muscle bundles isolated from LA did not affect myofilament Ca 2+ -sensitivity (LV: +0.26 ΔpCa 50 ; LA: +0.02 ΔpCa 50 ). X-ray diffraction revealed no CaM-associated alterations to interfilament spacing or equatorial intensity ratio (I 1,1 /I 1,0 ); however, a reversal in the M3 intensity was observed. In the reduced system, actin filament gliding speed driven by ventricular myosin increased by up to 46% in the presence of CaM and Ca 2+ , while atrial myosin showed a modest increase of ∼16%. Mechanistically, the resulting change in the gliding speed could be attributed to the binding of CaM to ELC binding site of myosin heavy chain. Notably, CaM’s presence displayed a more pronounced influence on the ventricular myosin as compared to the atrial myosin, which corroborated mechanical parameters of demembranted muscle bundles of atrial or ventricular origin. The results suggest that CaM enhanced the activation of β-myosin (predominantly in the LV), but not α-myosin (in the atria). This study provides scientific evidence for a novel tissue-specific physiological role of CaM in myofilament modulation.
Chastain et al. (2026) studied this question.