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Henk Granzier - One of the best experts on this subject based on the ideXlab platform.

  • sarcomere length dependent effects on ca2 troponin regulation in myocardium expressing compliant titin
    The Journal of General Physiology, 2019
    Co-Authors: Mei Methawasin, Henk Granzier, Bertrand C W Tanner, John R Solaro, Wenji Dong
    Abstract:

    Cardiac performance is tightly regulated at the cardiomyocyte level by sarcomere length, such that increases in sarcomere length lead to sharply enhanced force generation at the same Ca2+ concentration. Length-dependent activation of myofilaments involves dynamic and complex interactions between a multitude of thick- and thin-filament components. Among these components, troponin, myosin, and the giant protein titin are likely to be key players, but the mechanism by which these proteins are functionally linked has been elusive. Here, we investigate this link in the mouse myocardium using in situ FRET techniques. Our objective was to monitor how length-dependent Ca2+-induced conformational changes in the N domain of cardiac troponin C (cTnC) are modulated by myosin–actin cross-bridge (XB) interactions and increased titin compliance. We reconstitute FRET donor- and acceptor-modified cTnC(13C/51C)AEDANS-DDPM into chemically skinned myocardial fibers from wild-type and RBM20-deletion mice. The Ca2+-induced conformational changes in cTnC are quantified and characterized using time-resolved FRET measurements as XB state and sarcomere length are varied. The RBM20-deficient mouse expresses a more compliant N2BA titin isoform, leading to reduced Passive Tension in the myocardium. This provides a molecular tool to investigate how altered titin-based Passive Tension affects Ca2+-troponin regulation in response to mechanical stretch. In wild-type myocardium, we observe a direct association of sarcomere length–dependent enhancement of troponin regulation with both Ca2+ activation and strongly bound XB states. In comparison, measurements from titin RBM20-deficient animals show blunted sarcomere length–dependent effects. These results suggest that titin-based Passive Tension contributes to sarcomere length–dependent Ca2+-troponin regulation. We also conclude that strong XB binding plays an important role in linking the modulatory effect of titin compliance to Ca2+-troponin regulation of the myocardium.

  • Titin-Based Passive Tension is Increased in a Titin AI KO Mouse
    Biophysical Journal, 2014
    Co-Authors: Rebecca E. Slater, Mei Methawasin, Kirk R. Hutchinson, Henk Granzier
    Abstract:

    The giant sarcomeric protein titin spans the length of the half sarcomere and consists of an I-band region that functions as a molecular spring and a less well understood A-band region. Here we characterize a mouse model in which a portion of titin near the A-I junction has been removed(AIKO). We measured Passive stiffness using a muscle mechanics stretch-hold-release protocol in which a skinned fiber from the left ventricle papillary was stretched to a given sarcomere length(SL) within the physiological range, held for 90 seconds, and subjected to a sinusoidal frequency sweep. Active Tensions were measured at SL=2.0μm and SL=2.2μm in both tissue types. We found that both total and titin-based Passive stiffness was significantly higher in the AI KO compared to WT; at SL=2.3μm peak total Passive Tension was 43.5+/8.3mN/mm2 in the KO compared to 23.5+/-3.6mN/mm2 in the WT while peak titin-based Passive Tension was 28.7+/-7.0mN/mm2 in the AI KO compared to 13.8+/-2.0mN/mm2 in the WT. A similar trend was observed for total and titin-based steady state Passive Tensions. No significant differences in active Tensions were observed at either SL indicating no major changes to the thick filament or myofilament area; this suggests the Passive Tension difference is intrinsic to titin. The sinusoidal frequency sweep was used to quantify the vicious and elastic modulus. Viscous and elastic moduli are defined as (σ/e)sin(θ) and (σ/e)cos(θ) respectively where σ is stress, e is strain, and θ is the phase shift. We found that both the viscous modulus and the elastic modulus were higher in the AI KO at high frequencies. These results suggest that WT Passive Tension levels rely on an intact A-I junction; the removal of this region results in increased titin stiffness.

  • thick filament strain and interfilament spacing in Passive muscle effect of titin based Passive Tension
    Biophysical Journal, 2011
    Co-Authors: Thomas C Irving, Tanya Bekyarova, Gerrie P Farman, Norio Fukuda, Henk Granzier
    Abstract:

    We studied the effect of titin-based Passive Tension on sarcomere structure by simultaneously measuring Passive Tension and low-angle x-ray diffraction patterns on Passive fiber bundles from rabbit skinned psoas muscle. We used a stretch-hold-release protocol with measurement of x-ray diffraction patterns at various Passive Tension levels during the hold phase before and after Passive stress relaxation. Measurements were performed in relaxing solution without and with dextran T-500 to compress the lattice toward physiological levels. The myofilament lattice spacing was measured in the A-band (d1,0) and Z-disk (dZ) regions of the sarcomere. The axial spacing of the thick-filament backbone was determined from the sixth myosin meridional reflection (M6) and the equilibrium positions of myosin heads from the fourth myosin layer line peak position and the I1,1/I1,0 intensity ratio. Total Passive Tension was measured during the x-ray experiments, and a differential extraction technique was used to determine the relations between collagen- and titin-based Passive Tension and sarcomere length. Within the employed range of sarcomere lengths (∼2.2–3.4 μm), titin accounted for >80% of Passive Tension. X-ray results indicate that titin compresses both the A-band and Z-disk lattice spacing with viscoelastic behavior when fibers are swollen after skinning, and elastic behavior when the lattice is reduced with dextran. Titin also increases the axial thick-filament spacing, M6, in an elastic manner in both the presence and absence of dextran. No changes were detected in either I1,1/I1,0 or the position of peaks on the fourth myosin layer line during Passive stress relaxation. Passive Tension and M6 measurements were converted to thick-filament compliance, yielding a value of ∼85 m/N, which is several-fold larger than the thick-filament compliance determined by others during the tetanic Tension plateau of activated intact muscle. This difference can be explained by the fact that thick filaments are more compliant at low Tension (Passive muscle) than at high Tension (tetanic Tension). The implications of our findings are discussed.

  • heart failure decreases Passive Tension generation of rat diaphragm fibers
    International Journal of Cardiology, 2010
    Co-Authors: H W H Van Hees, Henk Granzier, Coen A C Ottenheijm, P N R Dekhuijzen, Leo M A Heunks
    Abstract:

    Abstract Background Diaphragm dysfunction is well-known to limit quality of life and prognosis of patients with heart failure (HF), but its underlying mechanisms are not well understood. In an animal model for HF we recently showed that impaired diaphragm contractility arises at the single fiber level and is associated with sarcomeric injuries. For optimal muscle function and sarcomeric stability Passive elastic structures, like titin, are indispensable. The current study aimed to investigate if impaired Passive elasticity contributes to diaphragm dysfunction in rats with heart failure. Methods Skinned muscle fibers were isolated from the diaphragm and soleus of rats with chronic HF, induced by left coronary artery ligation and of sham-operated rats. Passive Tension–length relationships were determined by applying segmental exTension tests. Immunofluorescence was performed on muscle cryosections using antibodies (T12) against a titin epitope near the Z-line. Titin content was determined by SDS-agarose-gel electrophoresis. Titin's mobility on gel was studied to detect changes in titin size. Results Passive Tension generation upon stretch was significantly reduced (>35%) in HF diaphragm fibers compared to sham. Immunostaining intensities against titin were reduced in diaphragm cryosections of HF rats compared to sham. Soleus fibers from HF and sham rats did not display differences, neither in Passive Tension nor in immunostaining. No differences in titin's size were detected in HF and sham diaphragm. Titin content, however, was significantly reduced (∼25%) in HF diaphragm. Discussion We conclude that in the diaphragm of HF rats, Passive elasticity is impaired, mainly resulting from titin loss.

  • pkc phosphorylation of titin s pevk element a novel and conserved pathway for modulating myocardial stiffness
    Circulation Research, 2009
    Co-Authors: Carlos Hidalgo, Siegfried Labeit, Marion L. Greaser, Bryan D Hudson, Julius Bogomolovas, Yi Zhu, Brian P Anderson, Henk Granzier
    Abstract:

    Rationale: Protein kinase C (PKC) regulates contractility of cardiac muscle cells by phosphorylating thin- and thick- filament-based proteins. Myocardial sarcomeres also contain a third myofilament, titin, and it is unknown whether titin can be phosphorylated by PKC and whether it affects Passive Tension. Objective: The purpose of this study was to examine the effect of PKC on titin phosphorylation and titin-based Passive Tension. Methods and Results: Phosphorylation assays with PKCα revealed that titin is phosphorylated in skinned myocardial tissues; this effect is exacerbated by pretreating with protein phosphatase 1. In vitro phosphorylation of recombinant protein representing titin’s spring elements showed that PKCα targets the proline – glutamate – valine – lysine (PEVK) spring element. Furthermore, mass spectrometry in combination with site-directed mutagenesis identified 2 highly conserved sites in the PEVK region that are phosphorylated by PKCα (S11878 and S12022); when these 2 sites are mutated t...

Richard L. Lieber - One of the best experts on this subject based on the ideXlab platform.

  • Differential Effects of 1 O-Hz and 50 Hz-Stimulation of the Tibialis Anterior on the Ipsilateral, Unstimulated Soleus Muscle
    2020
    Co-Authors: Richard L. Lieber, And Thomas D Ferro, Alan R Hargens&apos
    Abstract:

    Twelve rabbits were cast-immobilized for 4 weeks during which either lo-or 50-Hz stimulation was applied transcutaneously to the anterior compartment muscles. After the treatment period, tibialis anterior and soleus muscle contractile and histochemical properties were measured. Tibialis anterior stimulation at either 10 or 50 Hz had significantly different effects on the ipsilateral, unstimulated soleus muscles. Whereas soleus muscles of both groups demonstrated significant atrophy relative to nonstimulated, nonimmobilized soleus muscles, the soleus muscles from the 50-Hz group demonstrated significantly less atrophy than did the soleus muscles from the IO-Hz group as indicated by significantly greater muscle mass, maximum tetanic Tension, and fast fiber area. The results indicate that muscle stimulation may have beneficial effects on ipsilateral muscles that are Passively stretched secondary to stimulation. In addition, Passive Tension, not just muscle activation, appears to have an important role in regulating muscle size

  • muscle fibers bear a larger fraction of Passive muscle Tension in frogs compared with mice
    The Journal of Experimental Biology, 2018
    Co-Authors: Gretchen A Meyer, Richard L. Lieber
    Abstract:

    Differences in Passive muscle mechanical properties between amphibians and mammals have led to differing hypotheses on the functional role of titin in skeletal muscle. Early studies of frog muscle clearly demonstrated intracellular load-bearing by titin, but more recent structural and biological studies in mice have shown that titin may serve other functions. Here we present biomechanical studies of isolated frog and mouse fibers and fiber bundles to compare the relative importance of intracellular vs. extracellular load bearing in these species. Mouse bundles exhibited increased modulus compared with fibers on the descending limb of the length-Tension curve, reaching a 2.4-fold elevation at the longest sarcomere lengths. By contrast, frog fibers and bundles had approximately the same modulus at all sarcomere lengths tested. These findings suggest that, in contrast to frog muscle, titin does not bear a significant amount of the whole muscle Passive Tension in mammals.

  • effect of supraspinatus tendon injury on supraspinatus and infraspinatus muscle Passive Tension and associated biochemistry
    Journal of Bone and Joint Surgery American Volume, 2014
    Co-Authors: Morgan D Silldorff, Richard L. Lieber, Alexander D Choo, Anthony J Choi, Evie Lin, Austin J Carr, John G Lane, Samuel R. Ward
    Abstract:

    Rotator cuff musculature plays a vital role in stabilizing the shoulder joint and is a common site of injury, especially among the elderly1. Degenerative changes occur with increasing age2, but acute injury remains a problem for all age groups. Rotator cuff tears lead to weakness3, decreased range of motion4, pain, and functional deficiencies5. Harryman et al.4 and Gerber et al.6 reported that the integrity of the repair, not the size of the initial tear, is closely linked to the functional outcome of the rotator cuff repair. However, success rates for repairs are limited, in part, because of the changes in stiffness and retraction of the muscle and tendon after the tendon injury7. The difficulty in repairing traumatic massive rotator cuff tears has been documented as early as six weeks after the initial injury8. Data from human and animal models have suggested that whole muscle stiffness increases when the tendon is torn and as the severity of the tear increases6,9-14. Although increases in stiffness have been associated with whole muscle connective tissue content11, it remains unclear whether these changes are caused by fibrosis, shortened muscle fibers, or changes in the material properties of the fibers themselves15,16. Data from previous studies involving rabbit muscle have demonstrated a correlation between the molecular weight of titin and single fiber stiffness17, and some data have indicated that whole muscle collagen content is elevated in muscles with greater Passive Tension11. However, these adaptations have been poorly studied in rotator cuff disease in humans. The authors of a previous study compared the material properties of single fibers and fiber bundles from massive supraspinatus tears with single fibers and fiber bundles from the deltoid muscle18. Although the authors found no significant differences between the deltoid and supraspinatus muscles, this comparison with the deltoid is problematic because different human muscles have different Passive mechanical properties19, and their analytical method involved sarcomere lengths that were supraphysiologic. Therefore, the purpose of this current study was to compare the Passive mechanical properties of the supraspinatus and infraspinatus muscles with intact and torn supraspinatus tendons.

  • whole muscle length Tension relationships are accurately modeled as scaled sarcomeres in rabbit hindlimb muscles
    Journal of Biomechanics, 2011
    Co-Authors: Taylor M Winters, Richard L. Lieber, Mitsuhiko Takahashi, Samuel R. Ward
    Abstract:

    An a priori model of the whole active muscle length-Tension relationship was constructed utilizing only myofilament length and serial sarcomere number for rabbit tibialis anterior (TA), extensor digitorum longus (EDL), and extensor digitorum II (EDII) muscles. Passive Tension was modeled with a two-element Hill-type model. Experimental length-Tension relations were then measured for each of these muscles and compared to predictions. The model was able to accurately capture the active-Tension characteristics of experimentally-measured data for all muscles (ICC=0.88 ± 0.03). Despite their varied architecture, no differences in predicted versus experimental correlations were observed among muscles. In addition, the model demonstrated that excursion, quantified by full-width-at-half-maximum (FWHM) of the active length-Tension relationship, scaled linearly (slope=0.68) with normalized muscle fiber length. Experimental and theoretical FWHM values agreed well with an intraclass correlation coefficient of 0.99 (p<0.001). In contrast to active Tension, the Passive Tension model deviated from experimentally-measured values and thus, was not an accurate predictor of Passive Tension (ICC=0.70 ± 0.07). These data demonstrate that modeling muscle as a scaled sarcomere provides accurate active functional but not Passive functional predictions for rabbit TA, EDL, and EDII muscles and call into question the need for more complex modeling assumptions often proposed.

  • rotator cuff muscle architecture implications for glenohumeral stability
    Clinical Orthopaedics and Related Research, 2006
    Co-Authors: Samuel R. Ward, Jan Fridén, Laura H. Smallwood, Eric R Hentzen, Robert K Eastlack, Katherine A Burns, Donald C Fithian, Richard L. Lieber
    Abstract:

    We examined the architectural properties of the rotator cuff muscles in 10 cadaveric specimens to understand their functional design. Based on our data and previously published joint angle-muscle excursion data, sarcomere length operating ranges were modeled through all permutations in 75 masculine medial and lateral rotation and 75 masculine abduction at the glenohumeral joint. Based on physiologic cross-sectional area, the subscapularis would have the greatest force-producing capacity, followed by the infraspinatus, supraspinatus, and teres minor. Based on fiber length, the supraspinatus would operate over the widest range of sarcomere lengths. The supraspinatus and infraspinatus had relatively long sarcomere lengths in the anatomic position, and were under relatively high Passive Tensions at rest, indicating they are responsible for glenohumeral resting stability. However, the subscapularis contributed Passive Tension at maximum abduction and lateral rotation, indicating it plays a critical role in glenohumeral stability in the position of apprehension. These data illustrate the exquisite coupling of muscle architecture and joint mechanics, which allows the rotator cuff to produce near maximal active Tensions in the midrange and produce Passive Tensions in the various end-range positions. During surgery relatively small changes to rotator cuff muscle length may result in relatively large changes in shoulder function.

Wolfgang A Linke - One of the best experts on this subject based on the ideXlab platform.

  • differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts
    Cardiovascular Research, 2013
    Co-Authors: Sebastian Kotter, Wolfgang A Linke, Martina Krüger, Laurence Gout, Marion Von Frielingsalewsky, Anna Eliane Muller, Stefan Helling, Katrin Marcus, Cristobal Dos G Remedios
    Abstract:

    Aims Titin-based myofilament stiffness is defined by the expression levels of the cardiac titin-isoforms, N2B and N2BA, and by phosphorylation of the elastic titin domains N2-B unique sequence (N2-Bus) and PEVK. Phosphorylation of the N2-Bus by cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) decreases titin stiffness, whereas phosphorylation of the PEVK-domain by PKC increases it. We aimed to identify specific sites within the N2-Bus phosphorylated by PKA and PKG and to determine whether differential changes in titin domain phosphorylation could affect Passive stiffness in human failing hearts. Methods and results Using mass spectrometry, we identified seven partly conserved PKA/PKG-targeted phosphorylation motifs in human and rat N2-Bus. Polyclonal antibodies to pSer4185, pSer4010, and pSer4099 in the N2-Bus, and to pSer11878 in the PEVK-region were used to quantify titin-domain phosphorylation by western blot analyses of a set of human donor and failing hearts with similar titin-isoform composition. Passive Tension determined in skinned human myocardial fibre preparations was significantly increased in failing compared with donor hearts, notably at shorter sarcomere lengths where titin contributes most to total Passive Tension. Phosphorylation of Ser4185, Ser4010, and Ser4099 in the N2-Bus was significantly reduced in failing hearts, whereas phosphorylation of Ser11878 in the PEVK-region was increased compared with donor hearts. Conclusion We conclude that hypo-phosphorylation of the N2-Bus and hyper-phosphorylation of the PEVK domain can act complementary to elevate Passive Tension in failing human hearts. Differential changes in titin-domain phosphorylation may be important to fine-tune Passive myocardial stiffness and diastolic function of the heart.

  • protein kinase a phosphorylates titin in human heart muscle and reduces myofibrillar Passive Tension
    Journal of Muscle Research and Cell Motility, 2006
    Co-Authors: Martina Krüger, Wolfgang A Linke
    Abstract:

    Protein kinase-A (PKA) is activated during β-adrenergic stimulation of the heart and is known to phosphorylate several sarcomeric proteins including the giant polypeptide titin. A PKA phosphorylation site on titin is located within the N2B-unique sequence, which is present in the elastic segment of the two major isoforms of cardiac titin, N2B and N2BA, but not in the skeletal-muscle isoforms of the N2A-type. In bovine and rat cardiomyocytes, PKA-mediated phosphorylation decreases Passive Tension (PT), an effect ascribed to titin phosphorylation. Whether titin is phosphorylated by PKA upon β-adrenergic stimulation in human heart has not been shown to date. Here we report that PKA induces phosphorylation of N2B and N2BA titin isoforms, as well as a characteristic proteolytic fragment of titin, T2, in human donor hearts. The PKA-induced phosphorylation signals were stronger when myofilaments were first de-phosphorylated by protein phosphatase-1, suggesting inherent phosphorylation of titin in human heart. Titin phosphorylation was associated with a reduction in PT of skinned human cardiac strips; the relative decrease was higher at shorter than at longer physiological sarcomere lengths. The PKA-dependent PT drop was substantially larger when fibers were pre-treated with protein phosphatase-1, indicating that inherent phosphorylation of titin is important for the basal myocardial PT level. Mechanical measurements on isolated myofibrils from rat heart confirmed the PKA effect on Passive stiffness and also showed a more pronounced effect in the presence of reducing agent, DTT. In contrast, PKA did not alter the PT of single skinned rat diaphragm muscle fibers; however, the kinase was still able to phosphorylate the skeletal N2A-titin isoform, which lacks the N2B-unique sequence. Thus, an additional phosphorylation site in titin may exist outside the cardiac N2B-unique sequence. We conclude that PKA mediates phosphorylation of titin in normal human myocardium. Titin phosphorylation lowers titin-based Passive stiffness in heart but not in skeletal muscle.

  • Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts
    Circulation Research, 2004
    Co-Authors: Irina G. Makarenko, Christiane A. Opitz, Mark C. Leake, Ciprian Neagoe, Matthew H. Kulke, Judith K. Gwathmey, F. Del Monte, Roger J. Hajjar, Wolfgang A Linke
    Abstract:

    In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. In this study, we analyzed titin expression in left ventricles of 19 control human donors and 9 severely diseased (nonischemic) dilated cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, and quantitative RT-PCR. Both human-heart groups coexpressed smaller (approximately 3 MDa) N2B-isoform and longer (3.20 to 3.35 MDa) N2BA-isoforms, but the average N2BA:N2B-protein ratio was shifted from approximately 30:70 in controls to 42:58 in DCM hearts, due mainly to increased expression of N2BA-isoforms >3.30 MDa. Titin per unit tissue was decreased in some DCM hearts. The titin-binding protein obscurin also underwent isoform-shifting in DCM. Quantitative RT-PCR revealed a 47% reduction in total-titin mRNA levels in DCM compared with control hearts, but no differences in N2B, all-N2BA, and individual-N2BA transcripts. The reduction in total-titin transcripts followed from a decreased area occupied by myocytes and increased connective tissue in DCM hearts, as detected by histological analysis. Force measurements on isolated cardiomyofibrils showed that sarcomeric Passive Tension was reduced on average by 25% to 30% in DCM, a reduction readily predictable with a model of wormlike-chain titin elasticity. Passive-Tension measurements on human-heart fiber bundles, before and after titin proteolysis, revealed a much-reduced relative contribution of titin to total Passive stiffness in DCM. Results suggested that the titin-isoform shift in DCM depresses the proportion of titin-based stiffness by approximately 10%. We conclude that a lower-than-normal proportion of titin-based stiffness in end-stage failing hearts results partly from loss of titin and increased fibrosis, partly from titin-isoform shift. The titin-isoform shift may be beneficial for myocardial diastolic function, but could impair the contractile performance in systole.

  • basis of Passive Tension and stiffness in isolated rabbit myofibrils
    American Journal of Physiology-cell Physiology, 1997
    Co-Authors: Marc L Bartoo, Wolfgang A Linke, Gerald H. Pollack
    Abstract:

    By examining the mechanical properties of isolated skeletal and cardiac myofibrils in calcium-free, ATP-containing solution, we attempted to separate the stiffness contribution of titin filaments from that of weakly bound cross bridges. Efforts to enhance weak cross-bridge binding by lowering ionic strength were met by clear contractile responses. Even at low temperature, myofibrils bathed in low-ionic-strength relaxing solution generated increased force and exhibited sarcomere shortening, apparently caused by active contraction. At normal ionic strength, myofibril stiffness, estimated from the force response to rapid sinusoidal oscillations, increased steadily with sarcomere exTension up to a strain limit. No obvious stiffness contribution from weak cross bridges was detectable. Instead, the stiffness response, which was frequency dependent at all sarcomere lengths, was apparently generated by the viscoelastic titin filaments. During imposed stretch-hold ramps, both peak force/stiffness and the amount of subsequent stress relaxation increased with higher stretch rates, larger stretch amplitudes, and longer sarcomere lengths. We conclude that, for a truly relaxed myofibril, both Passive force and dynamic stiffness principally reflect the intrinsic viscoelastic properties of the titin filaments.

  • towards a molecular understanding of the elasticity of titin
    Journal of Molecular Biology, 1996
    Co-Authors: Wolfgang A Linke, Marc Ivemeyer, N Olivieri, Bernhard Kolmerer, J C Ruegg, Siegfried Labeit
    Abstract:

    Vertebrate striated muscle behaves elastically when stretched and this property is thought to reside primarily within the giant filamentous protein, titin (connectin). The elastic portion of titin comprises two distinct structural motifs, immunoglobulin (Ig) domains and the PEVK titin, which is a novel motif family rich in proline, glutamate, valine and lysine residues. The respective contributions of the titin Ig and the PEVK sequences to the elastic properties of the molecule have been unknown so far. We have measured both the Passive Tension in single, isolated myofibrils from cardiac and skeletal muscle and the stretch-induced translational movement of I-band titin antibody epitopes following immunofluorescent labelling of sites adjacent to the PEVK and Ig domain regions. We found that with myofibril stretch, I-band titin does not extend homogeneously. The Ig domain region lengthened predominantly during small stretch, but such lengthening did not result in measurable Passive Tension and might be explained by straightening, rather than by unfolding, of the Ig repeats. At moderate to extreme stretch, the main extensible region was found to be the PEVK segment whose unravelling was correlated with a steady Passive Tension increase. In turn, PEVK domain transition from a linearly extended to a folded state appears to be principally responsible for the elasticity of muscle fibers. Thus, the length of the PEVK sequence may determine the tissue-specificity of muscle stiffness, whereas the expression of different Ig domain motif lengths may set the characteristic slack sarcomere length of a muscle type.

Samuel R. Ward - One of the best experts on this subject based on the ideXlab platform.

  • effect of supraspinatus tendon injury on supraspinatus and infraspinatus muscle Passive Tension and associated biochemistry
    Journal of Bone and Joint Surgery American Volume, 2014
    Co-Authors: Morgan D Silldorff, Richard L. Lieber, Alexander D Choo, Anthony J Choi, Evie Lin, Austin J Carr, John G Lane, Samuel R. Ward
    Abstract:

    Rotator cuff musculature plays a vital role in stabilizing the shoulder joint and is a common site of injury, especially among the elderly1. Degenerative changes occur with increasing age2, but acute injury remains a problem for all age groups. Rotator cuff tears lead to weakness3, decreased range of motion4, pain, and functional deficiencies5. Harryman et al.4 and Gerber et al.6 reported that the integrity of the repair, not the size of the initial tear, is closely linked to the functional outcome of the rotator cuff repair. However, success rates for repairs are limited, in part, because of the changes in stiffness and retraction of the muscle and tendon after the tendon injury7. The difficulty in repairing traumatic massive rotator cuff tears has been documented as early as six weeks after the initial injury8. Data from human and animal models have suggested that whole muscle stiffness increases when the tendon is torn and as the severity of the tear increases6,9-14. Although increases in stiffness have been associated with whole muscle connective tissue content11, it remains unclear whether these changes are caused by fibrosis, shortened muscle fibers, or changes in the material properties of the fibers themselves15,16. Data from previous studies involving rabbit muscle have demonstrated a correlation between the molecular weight of titin and single fiber stiffness17, and some data have indicated that whole muscle collagen content is elevated in muscles with greater Passive Tension11. However, these adaptations have been poorly studied in rotator cuff disease in humans. The authors of a previous study compared the material properties of single fibers and fiber bundles from massive supraspinatus tears with single fibers and fiber bundles from the deltoid muscle18. Although the authors found no significant differences between the deltoid and supraspinatus muscles, this comparison with the deltoid is problematic because different human muscles have different Passive mechanical properties19, and their analytical method involved sarcomere lengths that were supraphysiologic. Therefore, the purpose of this current study was to compare the Passive mechanical properties of the supraspinatus and infraspinatus muscles with intact and torn supraspinatus tendons.

  • whole muscle length Tension relationships are accurately modeled as scaled sarcomeres in rabbit hindlimb muscles
    Journal of Biomechanics, 2011
    Co-Authors: Taylor M Winters, Richard L. Lieber, Mitsuhiko Takahashi, Samuel R. Ward
    Abstract:

    An a priori model of the whole active muscle length-Tension relationship was constructed utilizing only myofilament length and serial sarcomere number for rabbit tibialis anterior (TA), extensor digitorum longus (EDL), and extensor digitorum II (EDII) muscles. Passive Tension was modeled with a two-element Hill-type model. Experimental length-Tension relations were then measured for each of these muscles and compared to predictions. The model was able to accurately capture the active-Tension characteristics of experimentally-measured data for all muscles (ICC=0.88 ± 0.03). Despite their varied architecture, no differences in predicted versus experimental correlations were observed among muscles. In addition, the model demonstrated that excursion, quantified by full-width-at-half-maximum (FWHM) of the active length-Tension relationship, scaled linearly (slope=0.68) with normalized muscle fiber length. Experimental and theoretical FWHM values agreed well with an intraclass correlation coefficient of 0.99 (p<0.001). In contrast to active Tension, the Passive Tension model deviated from experimentally-measured values and thus, was not an accurate predictor of Passive Tension (ICC=0.70 ± 0.07). These data demonstrate that modeling muscle as a scaled sarcomere provides accurate active functional but not Passive functional predictions for rabbit TA, EDL, and EDII muscles and call into question the need for more complex modeling assumptions often proposed.

  • rotator cuff muscle architecture implications for glenohumeral stability
    Clinical Orthopaedics and Related Research, 2006
    Co-Authors: Samuel R. Ward, Jan Fridén, Laura H. Smallwood, Eric R Hentzen, Robert K Eastlack, Katherine A Burns, Donald C Fithian, Richard L. Lieber
    Abstract:

    We examined the architectural properties of the rotator cuff muscles in 10 cadaveric specimens to understand their functional design. Based on our data and previously published joint angle-muscle excursion data, sarcomere length operating ranges were modeled through all permutations in 75 masculine medial and lateral rotation and 75 masculine abduction at the glenohumeral joint. Based on physiologic cross-sectional area, the subscapularis would have the greatest force-producing capacity, followed by the infraspinatus, supraspinatus, and teres minor. Based on fiber length, the supraspinatus would operate over the widest range of sarcomere lengths. The supraspinatus and infraspinatus had relatively long sarcomere lengths in the anatomic position, and were under relatively high Passive Tensions at rest, indicating they are responsible for glenohumeral resting stability. However, the subscapularis contributed Passive Tension at maximum abduction and lateral rotation, indicating it plays a critical role in glenohumeral stability in the position of apprehension. These data illustrate the exquisite coupling of muscle architecture and joint mechanics, which allows the rotator cuff to produce near maximal active Tensions in the midrange and produce Passive Tensions in the various end-range positions. During surgery relatively small changes to rotator cuff muscle length may result in relatively large changes in shoulder function.

Chantal Perot - One of the best experts on this subject based on the ideXlab platform.

  • an index of spindle efficacy obtained by measuring electroneurographic activity and Passive Tension in the rat soleus muscle
    Journal of Neuroscience Methods, 2006
    Co-Authors: Cedric Rosant, Chantal Perot
    Abstract:

    Abstract While muscle spindle afferent discharges are known to change with altered muscle use, the way in which the changes in spindle discharge are affected by modifications to the elastic properties of the muscle–tendon unit remains to analyze. This paper describes a methodology to define, in the rat, a spindle efficacy index. This index relates the spindle afferent discharges recorded from electroneurograms (ENG) due to muscle stretch to the Passive elastic properties of the muscle–tendon unit quantified during the stretch imposed for the ENGs recordings. The stretches were applied to the rat soleus muscle after the Achilles tendon was severed. The spindle afferent discharges were characterized from the root mean square (RMS) values of electroneurograms (ENGs) recorded from the soleus nerve. The first step of the study was to validate the definition of dynamic and static indices (DI and SI) of spindle discharges from RMS-ENG as classically done when isolated afferents are studied. The slopes of the DI-stretch velocity or SI-stretch amplitude relationships gave the indices of spindle sensitivity under dynamic and static conditions, respectively. Incremental stiffness was calculated to describe the Passive elastic properties during the dynamic and static phases of ramp and hold stretches applied at different amplitudes and velocities. The spindle efficacy index (SEI) is the ratio between the indices of spindle sensitivity and incremental stiffness values. Both spindle discharges and incremental stiffness increased with stretch amplitude under dynamic and static conditions. The corresponding SEI values were constant whatever the stretch amplitude. This result validates the relationship between spindle discharges and Passive incremental stiffness. This method can be proposed to study, in the rat, the spindle function when the muscles are suspected to present changes in their neuromechanical properties.

  • an index of spindle efficacy obtained by measuring electroneurographic activity and Passive Tension in the rat soleus muscle
    Journal of Neuroscience Methods, 2006
    Co-Authors: Cedric Rosant, Chantal Perot
    Abstract:

    While muscle spindle afferent discharges are known to change with altered muscle use, the way in which the changes in spindle discharge are affected by modifications to the elastic properties of the muscle-tendon unit remains to analyze. This paper describes a methodology to define, in the rat, a spindle efficacy index. This index relates the spindle afferent discharges recorded from electroneurograms (ENG) due to muscle stretch to the Passive elastic properties of the muscle-tendon unit quantified during the stretch imposed for the ENGs recordings. The stretches were applied to the rat soleus muscle after the Achilles tendon was severed. The spindle afferent discharges were characterized from the root mean square (RMS) values of electroneurograms (ENGs) recorded from the soleus nerve. The first step of the study was to validate the definition of dynamic and static indices (DI and SI) of spindle discharges from RMS-ENG as classically done when isolated afferents are studied. The slopes of the DI-stretch velocity or SI-stretch amplitude relationships gave the indices of spindle sensitivity under dynamic and static conditions, respectively. Incremental stiffness was calculated to describe the Passive elastic properties during the dynamic and static phases of ramp and hold stretches applied at different amplitudes and velocities. The spindle efficacy index (SEI) is the ratio between the indices of spindle sensitivity and incremental stiffness values. Both spindle discharges and incremental stiffness increased with stretch amplitude under dynamic and static conditions. The corresponding SEI values were constant whatever the stretch amplitude. This result validates the relationship between spindle discharges and Passive incremental stiffness. This method can be proposed to study, in the rat, the spindle function when the muscles are suspected to present changes in their neuromechanical properties.