Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Kampourakis, Thomas; Sun, Yin-Biao; Irving, Malcolm

doi:10.1073/pnas.1602776113

Cited by 123 publications

(162 citation statements)

References 60 publications

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“…Although cross-bridge detachment is primarily considered an ATP-mediated event, this finding supports the theory that [Ca 2þ ] may influence myosin detachment through thin-filament interactions, wherein decreased [Ca 2þ ] promotes a stronger interaction between troponin-I and actin that favors myosin detachment (52). It is also possible that myosin attachment and detachment kinetics change with the number of cross-bridges available to engage with the thin filament due to Ca 2þ -regulated and/or tension-mediated activation pathways between the thick and thin filaments (53,54). This combination of slower cross-bridge attachment and faster detachment rates at submaximal [Ca 2þ ] may not significantly alter the overall cross-bridge cycling rate and shortening velocity in a muscle fiber.…”

Section: Discussionsupporting

confidence: 78%

“…As sarcomere length increases, greater forces are distributed throughout the sarcomere to stabilize myofilament lattice organization and diminish myofilament extensibility (56,60,61) with increasingly greater tension development in a muscle fiber. Recent studies also suggest that force-dependent or load-dependent activation pathways between the thick and thin filaments regulate the number of cross-bridges that are ''activated'' or ''primed'' for binding available actin-target sites (53,54). Thus, it is likely that these structural alterations to the myofilaments also influence load-dependent mechanisms of MgADP release to slow cross-bridge detachment.…”

Section: Discussionmentioning

confidence: 99%

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

Fenwick

Leighton

Tanner

2016

Biophysical Journal

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Actin-myosin cross-bridges use chemical energy from MgATP hydrolysis to generate force and shortening in striated muscle. Previous studies show that increases in sarcomere length can reduce thick-to-thin filament spacing in skinned muscle fibers, thereby increasing force production at longer sarcomere lengths. However, it is unclear how changes in sarcomere length and lattice spacing affect cross-bridge kinetics at fundamental steps of the cross-bridge cycle, such as the MgADP release rate. We hypothesize that decreased lattice spacing, achieved through increased sarcomere length or osmotic compression of the fiber via dextran T-500, could slow MgADP release rate and increase cross-bridge attachment duration. To test this, we measured cross-bridge cycling and MgADP release rates in skinned soleus fibers using stochastic length-perturbation analysis at 2.5 and 2.0 mm sarcomere lengths as pCa and [MgATP] varied. In the absence of dextran, the force-pCa relationship showed greater Ca 2þ sensitivity for 2.5 vs. 2.0 mm sarcomere length fibers (pCa 50 ¼ 5.68 5 0.01 vs. 5.60 5 0.01). When fibers were compressed with 4% dextran, the length-dependent increase in Ca 2þ sensitivity of force was attenuated, though the Ca 2þ sensitivity of the force-pCa relationship at both sarcomere lengths was greater with osmotic compression via 4% dextran compared to no osmotic compression. Without dextran, the cross-bridge detachment rate slowed by~15% as sarcomere length increased, due to a slower MgADP release rate (11.2 5 0.5 vs. 13.5 5 0.7 s À1 ). In the presence of dextran, cross-bridge detachment was~20% slower at 2.5 vs. 2.0 mm sarcomere length due to a slower MgADP release rate (10.1 5 0.6 vs. 12.9 5 0.5 s À1 ). However, osmotic compression of fibers at either 2.5 or 2.0 mm sarcomere length produced only slight (and statistically insignificant) slowing in the rate of MgADP release. These data suggest that skeletal muscle exhibits sarcomere-length-dependent changes in cross-bridge kinetics and MgADP release that are separate from, or complementary to, changes in lattice spacing.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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

Fenwick

Leighton

Tanner

2016

Biophysical Journal

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“…6 and 32 kPa (SL = 1.9 μm) and 42 kPa (SL = 2.3 μm) in table S1 of ref. 37. These low forces imply, according to the mechanosensing-based thick filament regulation, a correspondingly low fraction of motors in the on state, a fraction that may be either already present because of the preexisting disorder in the relaxed state or too low to be detected.…”

Section: Discussionmentioning

confidence: 99%

Myosin filament activation in the heart is tuned to the mechanical task

Reconditi

Caremani

Pinzauti

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

130

147

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The mammalian heart pumps blood through the vessels, maintaining the dynamic equilibrium in a circulatory system driven by two pumps in series. This vital function is based on the fine-tuning of cardiac performance by the Frank-Starling mechanism that relates the pressure exerted by the contracting ventricle (end systolic pressure) to its volume (end systolic volume). At the level of the sarcomere, the structural unit of the cardiac myocytes, the Frank-Starling mechanism consists of the increase in active force with the increase of sarcomere length (length-dependent activation). We combine sarcomere mechanics and micrometer-nanometer-scale X-ray diffraction from synchrotron light in intact ventricular trabeculae from the rat to measure the axial movement of the myosin motors during the diastole-systole cycle under sarcomere length control. We find that the number of myosin motors leaving the off, ATP hydrolysis-unavailable state characteristic of the diastole is adjusted to the sarcomere length-dependent systolic force. This mechanosensing-based regulation of the thick filament makes the energetic cost of the systole rapidly tuned to the mechanical task, revealing a prime aspect of the Frank-Starling mechanism. The regulation is putatively impaired by cardiomyopathycausing mutations that affect the intramolecular and intermolecular interactions controlling the off state of the motors. myosin filament mechanosensing | heart regulation | small-angle X-ray diffraction | cardiac muscle | Frank-Starling mechanism I n each sarcomere, the structural unit of the skeletal and cardiac muscles, myosin motors arranged in antiparallel arrays in the two halves of the thick myosin-containing filament work cooperatively, generating force and shortening by cyclic ATPdriven interactions with the interdigitating thin actin-containing filaments. The textbook model for the activation of contraction indicates that the binding to actin of myosin motors from the neighboring thick filament is controlled by a calcium-dependent structural change in the thin filament. However, in these muscles at rest, most of the myosin motors are in the off state and packed into helical tracks with 43-nm periodicity on the surface of the thick filaments (1-4), making them unavailable for binding to the thin filament and ATP hydrolysis (5, 6). Recent X-ray diffraction experiments on single fibers from skeletal muscle showed that, in addition to the canonical thin filament activation system, a thick filament mechanosensing mechanism provides a way for selective unlocking of myosin motors during high load contraction (7). This thick filament-based regulation has not yet been shown in cardiac muscle, in which several regulatory systems are significant. In contrast to skeletal muscle, during heart contraction, the internal concentration of Ca 2+ ([Ca 2+ ] i ) may not reach the full activation level, and thus, the mechanical response depends on both [Ca 2+ ] i and the sensitivity of the filaments to Ca 2+ (8, 9). For a given [Ca 2+ ] i , the maximal force i...

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“…HF with complicated pathogenesis is associated with loss of cardiac contractility, abnormalities in Ca 2+ handling and altered phosphorylation states of cardiac contractile regulatory protein 43, 44. Our previous study has elucidated that overexpression of miR‐1 repressed potential target proteins CaM and cMLCK, which attenuated the phosphorylation of CaMKII, cMyBP‐C and MLC2v, leading to impaired sarcomeric assembly and consequent heart dysfunction 11.…”

Section: Discussionmentioning

confidence: 99%

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

Zhang

Niu

et al. 2018

J Cellular Molecular Medi

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MicroRNA‐1 (miR‐1) stands out as the most prominent microRNA (miRNA) in regulating cardiac function and has been perceived as a new potential therapeutic target. Lycium barbarum polysaccharides (LBPs) are major active constituents of the traditional Chinese medicine based on L. barbarum. The purpose of this study was to exploit the cardioprotective effect and molecular mechanism of LBPs underlying heart failure. We found that LBPs significantly reduced the expression of myocardial miR‐1. LBPs improved the abnormal ECG and indexes of cardiac functions in P‐V loop detection in transgenic (Tg) mice with miR‐1 overexpression. LBPs recovered morphological changes in sarcomeric assembly, intercalated disc and gap junction. LBPs reversed the reductions of CaM and cMLCK, the proteins targeted by miR‐1. Similar trends were also obtained in their downstream effectors including the phosphorylation of MLC2v and both total level and phosphorylation of CaMKII and cMyBP‐C. Collectively, LBPs restored adverse structural remodelling and improved cardiac contractile dysfunction induced by overexpression of miR‐1. One of the plausible mechanisms was that LBPs down‐regulated miR‐1 expression and consequently reversed miR‐1‐induced repression of target proteins relevant to myocardial contractibility. LBPs could serve as a new, at least a very useful adjunctive, candidate for prevention and therapy of heart failure.

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Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments

Cited by 123 publications

References 60 publications

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

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

Myosin filament activation in the heart is tuned to the mechanical task

Lycium barbarum polysaccharides restore adverse structural remodelling and cardiac contractile dysfunction induced by overexpression of microRNA‐1

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