Interpreting cardiac muscle force-length dynamics using a novel functional model

Abstract

. Interpreting cardiac muscle force-length dynamics using a novel functional model. Am J Physiol Heart Circ Physiol 286: H1535-H1545, 2004; 10.1152/ ajpheart.01029.2003.-To describe the dynamics of constantly activated cardiac muscle, we propose that length affects force via both recruitment and distortion of myosin cross bridges. This hypothesis was quantitatively tested for descriptive and explanative validity. Skinned cardiac muscle fibers from animals expressing primarily ␣-myosin heavy chain (MHC) (mouse, rat) or ␤-MHC (rabbit, ferret) were activated with solutions from pCa 6.1 to 4.3. Activated fibers were subjected to small-amplitude length perturbations [⌬L(t)] rich in frequency content between 0.1 and 40 Hz. In descriptive validation tests, the model was fit to the ensuing force response [⌬F(t)] in the time domain. In fits to 118 records, the model successfully accounted for most of the measured variation in ⌬F(t) (R 2 range, 0.997-0.736; median, 0.981). When some residual variations in ⌬F(t) were not accounted for by the model (as at low activation), there was very little coherence (Ͻ0.5) between these residual force variations and the applied ⌬L(t) input function, indicating that something other than ⌬L(t) was causing the measured variation in ⌬F(t). With one exception, model parameters were estimated with standard errors on the order of 1% or less. Thus parameters of the recruitment component of the model could be uniquely separated from parameters of the distortion component of the model and parameters estimated from any given fiber could be considered unique to that fiber. In explanative validation tests, we found that recruitment and distortion parameters were positively correlated with independent assessments of the physiological entity they were assumed to represent. The recruitment distortion model was judged to be valid from both descriptive and explanative perspectives and is, therefore, a useful construct for describing and explaining dynamic force-length relationships in constantly activated cardiac muscle. muscle stiffness; cross-bridge recruitment; cross-bridge distortion; model validation; mouse; rat; ferret; rabbit MUSCLE LENGTH modulates cardiac muscle force development, and the resultant force-length relationship (FLR) is basic to the Frank-Starling mechanism of the heart. In general, however, muscle FLRs extend beyond the typical isometric twitching conditions under which force-length data are commonly collected to also include the force response to any length change during contraction. Thus descriptors of muscle FLR should also depict the dynamic force response to length changes that occur during contraction. One often-studied aspect of the dynamic FLR is the force response to sinusoidal length change in a constantly activated muscle fiber. Under these dynamic conditions, the amplitude and phase of the force response depends on both the frequency and amplitude of the sinusoidal length change. Dividing the steady-state sinusoidal force response by the sinusoidal length change yields...

Myosin MgADP Release Rate Decreases as Sarcomere Length Increases in Skinned Rat Soleus Muscle Fibers

“…1 reflect enzymatic cross-bridge cycling behavior that produces frequency-dependent shifts in the viscoelastic mechanical response during Ca 2þ -activated contraction. These B-and C-processes characterize work-producing (cross-bridge attachment) and work-absorbing (cross-bridge detachment) muscle mechanics, respectively (6,(24)(25)(26). The parameters B and C represent the mechanical stress from the cross-bridges (number of cross-bridges formed  mean cross-bridge stiffness), and the rate parameters 2pb and 2pc reflect cross-bridge kinetics that are sensitive to biochemical perturbations affecting enzymatic activity, such as [MgATP], [MgADP], or [P i ] (27).…”

COOH-terminal truncation of flightin decreases myofilament lattice organization, cross-bridge binding, and power output in Drosophila indirect flight muscle

“…Enzymatic cross-bridge cycling behavior produces a frequency dependence in the measured viscous and elastic modulus during Ca 2ϩ -activated contraction. This enzymatic behavior is represented by the B-and C-processes, which characterize work-producing (cross-bridge recruitment) and -absorbing (cross-bridge distortion) processes, respectively (6,16,24). The characteristic frequency b is correlated with the observed rate of myosin force production and scales proportionally with shifts in the frequency of maximal oscillatory work production (17,35), while c is related to the mean duration of cross-bridge attachment (24).…”

Interaction between myosin heavy chain and troponin isoforms modulate cardiac myofiber contractile dynamics

“…myofiber dynamics; contraction speed; heart rate THERE IS SUBSTANTIAL PROTEIN sequence heterogeneity among orthologous cardiac myosin heavy chain (MHC) and troponin (Tn) isoforms across different animal species (30). This sequence heterogeneity in regulatory contractile proteins significantly affects myofilament dynamics, as assessed by the force response to muscle length change in constantly activated cardiac myofibers, which exhibits two clearly separable processes (3,5,20,30,35): 1) a relatively fast force dynamic associated with myosin cross-bridge (XB) distortion and 2) a relatively slow force dynamic associated with recruitment of additional XB into force-bearing states. The dynamics of XB distortion are principally determined by the enzymatic kinetics of MHC, and the dynamics of XB recruitment are affected greatly by cooperative interactions between Tn actions and XB cycling kinetics (3, 5, 6, 30).…”

“…Our group (9) recently showed that differences in troponin T (TnT), a subunit of the Tn regulatory protein complex, affected the slow XB recruitment dynamic (9), whereas a shift from ␣-to ␤-MHC isoform in the rat heart affected both the slow XB recruitment dynamic and the fast XB distortion dynamic (5). Furthermore, there is interplay between TnT and MHC such that the effect of mutant TnT on both tension-dependent ATP consumption and the fast XB distortion dynamic were significantly influenced by a shift from ␣-to ␤-MHC isoform (34).…”

“…In the left ventricle of both mice and rats, propylthiouracil (PTU) treatment shifts the MHC isoform from predominantly ␣-to ␤-MHC without affecting the expression of other thin filament regulatory proteins (16,22,24,27,34). An ␣-to ␤-MHCinduced alteration in XB cycling kinetics changes cooperative interactions between XB-Tn and XB-XB, thus affecting contractile dynamics by modifying XB recruitment (3,5,6). Thus PTU-treated mice and rats offer a unique opportunity to study the MHC-Tn interaction effects on contractile dynamics, especially given the availability of recombinant Tn for these two species.…”