At the subcellular level, the Frank-Starling law of the heart is described by an increase in calcium sensitivity and force with increased sarcomere length (SL). We examine how this relationship is affected by a dilated cardiomyopathy-associated mutation in tropomyosin (D230N, denoted Tm
D230N
) by measuring contractility of intact and permeabilized cardiac muscle preparations at short (2.0 μm) and long (2.3 μm) SL. Transgenic mouse hearts containing the Tm
D230N
mutation have significantly dilated hearts and reduced cardiac output by ~6 months of age. Intact trabeculae were electrically stimulated and paced at 1 Hz with oxygenated solution (30°C) circulating through the experimental chamber, and permeabilized preparations were bathed in solutions (15°C) of progressively increased [Ca
2+
] for measures of steady-state force. For intact muscle we found that the Tm
D230N
mutation results in significantly reduced twitch forces at SL 2.0 and 2.3 μm relative to wild-type (WT). Also, WT trabeculae displayed a significant increase in twitch force upon increase in SL (as expected) but Tm
D230N
trabeculae did not, demonstrating a loss of SL dependence of contraction. In permeabilized preparations, maximal activation (pCa 4.5) of both WT and Tm
D230N
preparations exhibited significant SL-dependent increases in force. However, at submaximal Ca
2+
(pCa 5.8), where the heart operates, WT preparations had significant increases in force with increasing length (comparing SL 2.0 to 2.3 μm), while this length-dependence of force augmentation in Tm
D230N
was absent. The increase in pCa
50
(pCa that produces half-maximal force) going from SL 2.0 to 2.3 μm was significantly less for Tm
D230N
preparations compared to WT, owing to a significantly smaller increase in pCa
50
at SL 2.3 μm (the pCa
50
at SL 2.0 μm was not significantly different between WT and Tm
D230N
). These results suggest that the Tm
D230N
mutation limits an increase in the Ca
2+
sensitivity of contraction as the muscle lengthens by damping thin filament activation. To further examine length-dependent effects of the Tm
D230N
mutation, future experiments will test conditions that augment cross-bridge binding/inhibition, and other models of dilated cardiomyopathy that inhibit thin filament activation. Funding: HL111197
Cardiac Thin Filament Activation Modulation by Stretch