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PubMed2026

YAP Promotes Microtubule Growth to Facilitate Sarcomere Disassembly in Adult Cardiomyocytes.

BACKGROUND: Mature mammalian cardiomyocytes (CMs) develop compact sarcomeric structures that inhibit proliferation. Consequently, CMs must dedifferentiate to a fetus-like state, which is accompanied by sarcomere disassembly, to enable successful cytokinesis. However, the regulation and coordination of CM dedifferentiation, cell cycle progression, and sarcomere reorganization remain unclear. METHODS: We generated adenovirus and adeno-associated virus (MyoAAV) vectors expressing YAP5SA and YAP5SA-S94A under Xon control for LMI070-inducible protein expression. We also developed MyoAAV-cTnT-Tuba1b-shRNA-miR30 for cardiomyocyte-specific knockdown of Tuba1b. These tools were used to investigate CM dedifferentiation and proliferation and sarcomere disassembly. We also performed Cleavage Under Targets and Release Using Nuclease to map the genome-wide binding sites of YAP5SA and YAP5SA-S94A in combination with RNA sequencing to identify YAP target genes. In addition, time-course live-imaging analysis was used to evaluate microtubule and sarcomere dynamics in adult CMs. RESULTS: We show that microtubule expression and network density decline with cardiac maturation. Overexpression of YAP5SA, a constitutively active YAP mutant, promotes microtubule growth by stabilizing microtubule dynamics, leading to CM dedifferentiation, cell cycle re-entry, and sarcomere disassembly. In contrast, colchicine blocks these processes and significantly attenuates YAP-induced cardiac regeneration. Live imaging reveals a distinct mode of sarcomere disassembly driven by enhanced microtubule polymerization, wherein microtubule plus-ends directly interact with α-actinin and displace α-actinin fragments, thereby facilitating sarcomere breakdown. Furthermore, the YAP5SA-S94A mutation, which disrupts the YAP and TEA domain interaction, significantly reduces YAP5SA-induced microtubule growth, sarcomere disassembly, and cell cycle activity. Mechanistically, cleavage under targets and release using nuclease combined with RNA sequencing identified direct YAP targets, including Ajuba and Tuba1b, which are critical for microtubule growth. CM-specific knockdown of Tuba1b attenuates YAP-driven sarcomere disassembly. CONCLUSIONS: These findings identify microtubule networks as an essential regulator modulating CM dedifferentiation and sarcomere reorganization, which is critical for CM cytokinesis and cardiac regenerative repair.

Animals↗

PubMed1977

The passive electrical properties of frog skeletal muscle fibres at different sarcomere lengths.

1. The passive electrical properties of frog skeletal muscle fibres have been measured at a number of different sarcomere lengths (from 2-1 to 4-0 micron). The geometrical outline of each fibre was determined from optical cross-sections and sarcomere length was measured by laser beam diffraction. 2. When fibres were stretched to long sarcomere lengths the membrane capacity, Cm, of both normal and detubulated (glycerol-treated) fibres was significantly less than the Cm of fibres at rest length. A significant reduction in membrane conductance of fibres held at long sarcomere lengths was only seen with detubulated fibres. 3. Membrane capacity and membrane conductance have a significant dependence on the cross-sectional area of normal fibres but are independent of cross-sectional area after detubulation. 4. It has been shown that membrane geometry depends on the sarcomere length of the fibre and it is suggested that the passive membrane properties are related to sarcomere length because they depend on membrane geometry. 5. The specific membrane capacity, calculated from the data from detubulated fibres, is 0-8 micronF/cm2. 6. The internal resistivity, Ri, of normal fibres, also depends on sarcomere length between 2-1 and 3-0 micron. At a sarcomere length of 2-1 micron the average Ri is 122 +/- 3 omega. cm (mean +/- S.E. of mean) and at a sarcomere length of 3-0 micron the average Ri is 210 +/- 17 omega. cm (mean +/- S.E. of mean). No further increase in Ri was observed with further increases in sarcomere length.

Animals↗

PubMed1978

Cross-bridge detachment and sarcomere 'give' during stretch of active frog's muscle.

1. A study has been made of the tension responses and sarcomere length changes produced by servo-controlled stretches applied to isometrically contracting frog muscle. Sarcomere lengths were monitored by cine-photography of diffiraction spectra obtained by illuminating a small area of muscle with a laser. 2. The tension increment produced by a ramp-and-hold stretch of approximately 1 mm (ca. 4% of the muscle length) comprises three phases whose limits are defined by two points, S1 and S2, where the slope of the response decreases abruptly. S1 and S2 correspond to extensions of 0.13 and 1.2% of the muscle length. 3. Movements of the first order spectra relative to the zero order recorded during stretch reveal that S2 coincides with an abrupt elongation of the sarcomeres. This is termed sarcomere 'give' and it occurs when the filaments are displaced by 11-12 nm from their steady-state (isometric) position. 4. The stiffness of the sarcomeres, Es, up to S2 decreases with increasing sarcomere length. The maximum force sustained by the muscle at S2, PS2, also shows an inverse dependence on sarcomere length. Both Es and PS2 fall to zero at an extrapolated sarcomere spacing of 3.6-3.7 micrometer, coinciding with the length at which the actin and myosin filaments no longer overlap. 5. The ratio PS2/P0 (where P0 = maximum isometric tension) varies with temperature and speed of stretch. It increases with increasing speeds of stretch until a certain critical velocity, Vc, is reached, beyond which it is almost independent of any further increase. Vc has a positive temperature coefficient, increasing 5-6 in the range 0-30 degrees C (Q10 = 1.8). There is a positive correlation between the maximum speed of isotonic shortening (Vmax.) and Vc in different muscles. 6. Sarcomere 'give' during stretch is considered to be due to forcible detachment of cross-bridges between the actin and myosin filaments. This results in recoil of the extended series elastic elements in the muscle at the expense of the sarcomers. The amount of filament displacement required to induce sarcomere 'give' (11-12 nm) is thought to represent the range of movement over which a cross-bridge can remain attached to actin during a stretch.

Actins↗

PubMed1978

The sarcomere length-tension relation in skeletal muscle.

Tension development during isometric tetani in single fibers of frog semitendinosus muscle occurs in three phases: (a) in initial fast-rise phase; (b) a slow-rise phase; and (c) a plateau, which lasts greater than 10 s. The slow-rise phase has previously been assumed to rise out of a progressive increase of sarcomere length dispersion along the fiber (Gordon et al. 1966. J. Physiol. [Lond.]. 184:143--169;184:170--192). Consequently, the "true" tetanic tension has been considered to be the one existing before the onset of the slow-rise phase; this is obtained by extrapolating the slowly rising tension back to the start of the tetanus. In the study by Gordon et al. (1966. J. Physiol. [Lond.] 184:170--192), as well as in the present study, the relation between this extrapolated tension and sarcomere length gave the familiar linear descending limb of the length-tension relation. We tested the assumption that the slow rise of tension was due to a progressive increase in sarcomere length dispersion. During the fast rise, the slow rise, and the plateau of tension, the sarcomere length dispersion at any area along the muscle was less than 4% of the average sarcomere length. Therefore, a progressive increase of sarcomere length dispersion during contraction appears unable to account for the slow rise of tetanic tension. A sarcomere length-tension relation was constructed from the levels of tension and sarcomere length measured during the plateau. Tension was independent of sarcomere length between 1.9 and 2.6 microgram, and declined to 50% maximal at 3.4 microgram. This result is difficult to reconcile with the cross-bridge model of force generation.

Animals↗

PubMed1979

Sarcomere length-resting tension relation in single frog atrial cardiac cells.

It generally has been thought that the relatively high resting tension characteristic of cardiac tissue resides in structures (collagen, elastin) external to the individual cardiac cells, but the evidence to support this conclusion has been indirect, since the resting tension of intact single cardiac cells has not been determined previously. The purpose of the present investigation was to determine the resting tension (stress)-sarcomere length relationships of single intact frog atrial cells. For tension determinations, a single cell was attached between two poly-L-lysine coated glass beams; one beam served as a compliant calibrated cantilevered force beam, and length changes were imposed on the cell by movement of the other beam. Coventional bright-field light microscope techniques were used to view the cell, the sarcomere pattern within the cell, and the position of the force beam. The resting tension of the intact cell increased from a value of about 10 nN at a sarcomere length of 2.35 microns to a value of about 130 nN at a sarcomere length of 3.45 microns. Lagrangian and Eulerian resting stress-sarcomere length relationships were computed from the resting tension-sarcomere length relationships. The Lagrangian stress increased from a value of about 0.6 mN/mm2 at a sarcomere length of 2.35 microns to a value of about 7 mN/mm2 at a sarcomere length of 3.45 microns. These values of stress are about 8- to 30-fold less than those previously reported for intact frog atrial tissue and indicate that the resting tension of intact frog atrial preparations resides primarily in structures external to the individual cardiac cell.

Animals↗

PubMed1979

Sarcomere length-tension relations of frog skinned muscle fibres during calcium activation at short lengths.

1. Single twitch fibres were isolated from anterior tibial muscles of the frog, Rana pipiens. The relationship between sarcomere length and steady tetanic tension at 5 degrees C was obtained from these living fibres in the range of sarcomere lengths between about 2.2 and 1.3 microns . These fibres were then either mechanically or chemically skinned. 2. Segments were cut from the skinned fibres and mounted in an experimental chamber using a technique designed to minimize segment compliance at the points of attachment. A piece approximately 1 mm in length remained exposed to the bathing solution. 3. The segments were photographed through a light microscope at magnifications of about 460 or 110 X during activation and relaxation, so that the sarcomere lengths could be determined from a part or the whole of the segment. Activations were done with solutions of pCa either 5.49 or 6.09 and at a temperature of 5 degrees C. Fibre segments which developed striation pattern irregularities during contraction were rejected. 4. The sarcomere length-tension relation obtained from these segments in the sarcomere length range 1.3-2.2 microns was similar to that obtained from the same fibres while still living. The results were similar at the two values of pCa used. 5. These results do not support the view that sarcomere length dependent variation in the amount of calcium which is released during tetanic stimulation is a major determinant of the form of the length-tension relation in living muscle fibres at sarcomere lengths less than about 2.0 microns.

Animals↗

PubMed1979

Transverse sarcomere splitting. A possible means of longitudinal growth in crab muscles.

Transversely split sarcomeres are seen in mouthpart muscles of the blue crab in the electron microscope. Sarcomeres split only at the H zone. Two new sarcomeres are formed by a Z disk which appears in the H zone of the splitting sarcomere. Splitting may involve breaking of the thick filaments in the H zone, elongation of these filaments, and formation of both new actin filaments and Z-disk materials, Sarcomere splitting would allow longitudinal growth of muscle cells without lengthening of sarcomeres and concomitant changes in contractile properties.

Animals↗

PubMed1979

Sarcomere motion in isolated cardiac cells.

Computerized image-analysis techniques have been employed to examine the sarcomere dynamics of isolated mammalian cardiac myocytes. The cells were prepared by perfusion of adult rabbit hearts with hyaluronidase-collagenase solutions; they exhibited phasic contractions in the presence of 10(-6) M Ca2+. The dissociated cells were visualized by phase microscopy and a video camera interfaced in a minicomputer. Digitized cell images were processed by an algorithm utilizing signal averaging and contrast enhancement to yield data showing individual sarcomere position and shortening vs. time, so that patterns of sarcomere activation could be observed in spontaneously contracting cells. Compared to records of whole-cell shortening and of striation displacement, computerized image analysis provided a much more faithful indication of time course and sequence of sarcomere shortening. Spontaneously contracting cells showed sequential sarcomere shortening beginning at one end and propagating longitudinally with a constant velocity, typically at 100--150 micron/s for beat rates of 40 min-1. Velocities of initial sarcomere shortening appeared to increase with elevated Ca2+. These observations are consistent with a regenerative mechanism of calcium-induced calcium release.

Animals↗

PubMed1979

The variation of characteristics of twitch and tetanic contractions with sarcomere length in isolated muscle fibres of the frog.

The relation between sarcomere length, tension and time course of tension development in twitch and tetanic contractions at 20 degrees C was determined for isolated fibres from the semitendinosus muscle of the frog (Rana esculenta). In twenty fibres at about 2.15 micron sarcomere length, the peak twitch tension, the maximum tetanic tension and the twitch/tetanus ratio ranged, respectively, from 0.22 to 1.6 kg/cm2, from 2.13 o 3.96 kg/cm2 an from 0.07 to 0.53. The peak twitch tension was found to be: i) directly correlated with the twitch/tetanus ratio and the time to the peak of the first derivative of the twitch tension, ii) inversely correlated with the time to the peak of the first derivative of tetanic tension. No significant correlation was found between the maximal tetanic tension and the peak twitch tension or the twitch/tetanus ratio. Peak twitch tension and twitch/tetanus ratio were not correlated with the fibre cross-sectional area which ranged from 1.052 to 6,283 micron2. Sarcomere length-tension curves for twitch and tetanic isometric contractions at 20 degrees C were determined in twelve fibres. Increases in sarcomere length from about 2.15 to 2.85 micron produced, depending on the peak twitch tension or the twitch/tetanus ratio at about 2.15 micron, either decrease and no change or increase in peak twitch tension, but constantly enhanced the twitch/tetanus ratio and the degree of this potentiation was inversely correlated with the twitch/tetanus ratio at 2.15 micron. Increase in sarcomere length above 2.15 micron did not alter the course of the early development of twitch and tetanic tensions, reduced considerably the variation in peak twitch tension and twitch/tetanus ratio, without altering that of tetanic tension and swamped the correlation between the peak twitch tension and the time to peak of the differentiated twitch tension. However, the peak twitch tension at about 2.85 micron resulted to be directly correlated with the peak twitch tension at about 2.15 micron and in addition the relative length-dependent change in the time of the peak of the first derivative of the twitch tension resulted to be directly correlated with the relative length-dependent change in the peak twitch tension. It is concluded that both the duration of the active state and the rate factors of activation contribute to the determining of the large variation in peak twitch tension at about 2.15 micron, whereas the length-dependent increase in twitch/tetanus ratio appears to be mainly determined by prolongation of the active state duration.

Animals↗

PubMed1977

Light diffraction studies of sarcomere dynamics in single skeletal muscle fibers.

A position-sensitive optical diffractometer has been used to examine the diffraction spectra produced by single skeletal muscle fibers during twitch and tetanic contraction. First-order diffraction lines were computer-analyzed for mean sarcomere length, line intensity, and percent dispersion in sarcomere length. Line intensity was observed to decrease rapidly by about 60 percent during a twitch, with an exponential recovery to resting intensity persisting well beyond cessation of sarcomere shortening; recovery was particularly prolonged at zero myofilament overlap. A number of single fibers at initial lengths from 2.5 to 3.5 MICRON EXHIBITED a splitting of the first-order line into two or more components during relaxation, with components merging back into a single peak by 200 ms after stimulation. This splitting reflects the asynchronous nature of myofibrillar relaxation within a single fiber. During tetanus, the dispersion decreased by more than 10 percent from onset to plateau, implying a gradual stabilization of sarcomeres.

Animals↗

PubMed1978

Preparative study on the isolation of single sarcomeres from rabbit skeletal muscle.

Single sarcomeres were prepared from fresh rabbit myofibrils by digestion with a calcium-activated factor (CAF). The rabbit single sarcomere has functional properties quite similar to those of single sarcomeres obtained from chicken muscle by a usual method. Thus it was found that the single sarcomeres obtained by CAF digestion were useful as a muscle model, though they were not completely intact.

Actinin↗

PubMed1979

Formation of sarcomeres in the embryonic heart of the lobster.

Cardiomyoblasts in the myocardium of embryonic lobsters at 3-4 weeks and 6 months of development were examined with the transmission electron microscope in order to describe the events in the formation of sarcomeres in a neurogenic cardiac system. Thick and thin myofilaments appear first in the cell periphery near the sarcolemma. They align in parallel in a sequential fashion to form consecutive sarcomeric units. Well-defined A and I bands appear before any semblance of a Z line is present. The initial sarcomere is anchored to the sarcolemma by the insertion of thin myofilaments into a region of electron dense material associated intimately with the sarcolemma. Myofibrils grow outward in several planes away from the electron-dense regions of membrane that serve as focal points for myofibril formation.

Animals↗

PubMed1979

Sarcomere length effects on the Sr2+- and Ca2+-activation curves in skinned frog muscle fibres.

1. A procedure recently described to produce rapid changes in [Ca2+] and [Sr2+] within the whole cross-section of skinned muscle preparations (Moisescu, D.G. (1976) Nature 262, 610--613, and Moisescu, D.G. and Thieleczek, R. (1978) J. Physiol. 275, 241--262) has enabled us to obtain whole Ca2+- or Sr2+-activation curves at different sacromere lengths with the same preparation. 2. The maximal isometric force response was found to be very similar in Ca2+-and Sr2+-buffered solutions for otherwise identical conditions. 3. The change in sarcomere length between approx. 2.2 and 2.6 micron reversibly shifted both the Ca2+- and the Sr2+-activation curves by approx. 0.1 log units towards lower concentrations of the activator, without affecting their shape. However, the change in sarcomere length in the range above 2.6 micron did not have an effect upon the relative isometric force response-pCa (and -pSr) relationship. 4. All the Ca2+- and Sr2+-activation curves present a similar steepness and indicate that the relative isometric force increases from approx. 10 to 90% if the concentration of the activator is increased 3-fold. 5. The half time for force development in these experiments did not appear to be influenced by the length of the sarcomeres. 6. A potentiometric method for determining the apparent affinity constants of Ca2+, Mg2+ and Sr2+ to EGTA and ATP under various conditions is described.

Animals↗

PubMed1979

The effect of sarcomere length and stretching on the rate of ATP splitting in glycerinated rabbit psoas muscle fibers.

The effect of sarcomere length and stretching on the tension and the rate of ATP splitting was studied using small fiber bundles from glycerinated rabbit psoas muscle. The rate of ATP slitting was determined by measuring ADP production, while the tension development in response to a contracting solution (at pCa 5.3) was recorded in the same preparation. The isometric tension developed by the preparation decreased when the sarcomere length was increased. The decrease of tension development was accompanied by a decrease in the rate of ATP splitting. If a preparation exerting steady isometric tension was stretched by 5--10% at a velocity of 0.1 mm/s, the rate of ATP splitting was increased after stretching, while the steady isometric tension attained after stretching was also higher than the initial value. The extent of the excess ATP splitting caused by stretching decreased with increasing sarcomere length. These results suggest that the rate of the interaction cycle between actin and myosin molecules may increase as a result of stretching.

Adenosine Triphosphatases↗

PubMed1979

The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres.

1. The velocity of shortening at zero load was studied during fused tetanic contractions and single twitches in isolated skeletal muscle fibres of Rana temporaria. 2. The technique used for determination of the speed of unloaded shortening consisted of a series of quick releases of different amplitudes applied at a given instant during activity. The time, delta t, needed for the fibre to take up the slack was plotted against the amplitude of release, delta L. The slope of the straight line relating delta t-delta L provided a measure of the velocity of shortening at zero load, V0. 3. V0 was compared with force-velocity data obtained at finite loads (load-clamp recordings). The predicted velocity of shortening at zero load, derived by hyperbolic extrapolation from velocities at low and intermediate loads, was not significantly different from V0. 4. The temperature dependence of isometric force and of shortening velocity was investigated between 2 and 12 degrees C in the same fibres. Q10 was 2.67 +/- 0.07 (S.E. of mean, n = 6) for V0 and 1.24 +/- 0.01 for tetanic force. 5. The velocity of unloaded shortening was determined at different sarcomere lengths in the range 1.4--3.1 microns. V0 was constant between 1.65 microns and approximately 2.7 microns. It decreased below 1.65 microns and increased above 2.7 microns. 6. The decrease in velocity at short sarcomere lengths probably reflects an increase of the passive resistance to shortening. The increase in velocity at long sarcomere lengths can be accounted for by the passive compressive force that is produced by the parallel elastic elements of the prestretched fibre. 7. V0 was determined at the peak of the twitch and during the plateau of the fused tetanus in the same fibre. Whereas the peak twitch force varied between 38 and 85% of the tetanic tension in the different fibres (mean: 71 +/- 5%, n = 8), V0 during the twitch was 99 +/- 2% of the value recorded during the tetanus. Depression of the isometric twitch amplitude to 10% of the control value by dantrolene did not cause any significant reduction of V0.

Animals↗

PubMed1978

The relaxation of sarcomeres in ischemic injury of myocardium.

Polarization-microscopic and micrometric investigations of the myocardium during infarction at autopsy and in experimental ischemic conditions, has shown that one of the earliest and most typical morphological signs of ischemic myocardium is sarcomere relaxation. The latter is expressed by the loss of contractility of muscle cells in life time and in strongly frozen corpses, and due to the effects of fixatives. Increase of the percentage of relaxed sarcomeres parallels the duration of experimental ischemia and the time after myocardial infarction. This allows the indirect calculation of irreversible cell change.

Animals↗

PubMed1979

Decrease of muscle extensibility and reduction of sarcomere number in soleus muscle following a local injection of tetanus toxin.

Slow soleus muscle in guinea pig developed within 4--6 days after local injection of a sublethal dose of tetanus toxin and 2--4 days after the first signs of local tetanus, a myostatic contracture characterized by a change in the passive tension--lengthening curve associated with a considerable decrease of the sarcomere number. It was demonstrated by clinical and EMG investigations that the soleus did have a tetanic spasm at least within the 2--4 day period of observation. When local tetanus was confined to slow soleus by functional suppression of rapid gastrocnemius and ankle flexor muscles, the decrease of the sarcomere number still persisted. This decrease failed to occur after section of the nerve supplying the soleus when associated with an injection of the tetanus toxin, and was much greater than when the soleus was passively shortened for the same period of time by plaster cast.

Animals↗

PubMed2026

PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes.

BACKGROUND: PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk-mitochondrial coupling driven by loss of PGM1-LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function. METHODS: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays. RESULTS: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy. CONCLUSION: Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.

Humans↗