The heart boosts its pumping force in systole as the volume entering during diastole increases—a phenomenon known as the Frank–Starling law. A key molecular underpinning is length‑dependent activation of myofilaments. This review organizes a two‑step model: (i) titin‑mediated lattice narrowing acts as the trigger, and (ii) the troponin–tropomyosin switch on the thin filament ultimately sets force output.
Beyond the rate‑limiting role of Ca²⁺, the authors show that phosphorylation states and genetic mutations of troponin I/T can shift the on–off equilibrium, sharpening or blunting the length‑dependence gradient. They discuss how the damped Frank–Starling response observed in heart‑failure progression may stem from degeneration or dysregulated phosphorylation of thin‑filament regulatory proteins, drawing on evidence from recent transgenic models and patient samples.
The review further highlights how titin‑isoform switching and viscoelastic modifications via PKC/PKA pathways synergize with cooperative thin‑filament activation to govern contractile dynamics—insights that directly expand therapeutic targets for heart failure. By surveying the mechano‑chemical coupling within the sarcomere, the article serves as a compass for future drug discovery.
Article information & citation
Fuyu Kobirumaki‑Shimozawa, Takahiro Inoue, Seine A Shintani, Kotaro Oyama, Takako Terui, Susumu Minamisawa, Shin’ichi Ishiwata, Norio Fukuda. Cardiac thin filament regulation and the Frank–Starling mechanism. The Journal of Physiological Sciences 64 (4), 221‑232 (2014).