scholarly journals Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv

2019 ◽  
Vol 20 (20) ◽  
pp. 5008
Author(s):  
Eun-Jeong Lee ◽  
Justin Kolb ◽  
Darren T. Hwee ◽  
Fady I. Malik ◽  
Henk L. Granzier
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Isometric Force ◽  
Functional Characterization ◽  
Nemaline Myopathy ◽  
Diaphragm Muscle ◽  
Fast Skeletal Muscle ◽  
Shortening Velocity ◽  
Complex Load ◽  
Maximal Stimulation

Respiratory failure due to diaphragm dysfunction is considered a main cause of death in nemaline myopathy (NM) and we studied both isometric force and isotonic shortening of diaphragm muscle in a mouse model of nebulin-based NM (Neb cKO). A large contractile deficit was found in nebulin-deficient intact muscle that is frequency dependent, with the largest deficits at low–intermediate stimulation frequencies (e.g., a deficit of 72% at a stimulation frequency of 20 Hz). The effect of the fast skeletal muscle troponin activator (FSTA) tirasemtiv on force was examined. Tirasemtiv had a negligible effect at maximal stimulation frequencies, but greatly reduced the force deficit of the diaphragm at sub-maximal stimulation levels with an effect that was largest in Neb cKO diaphragm. As a result, the force deficit of Neb cKO diaphragm fell (from 72% to 29% at 20 Hz). Similar effects were found in in vivo experiments on the nerve-stimulated gastrocnemius muscle complex. Load-clamp experiments on diaphragm muscle showed that tirasemtiv increased the shortening velocity, and reduced the deficit in mechanical power by 33%. Thus, tirasemtiv significantly improves muscle function in a mouse model of nebulin-based nemaline myopathy.

scholarly journals Corticosteroid effects on isotonic contractile properties of rat diaphragm muscle

1997 ◽  
Vol 83 (4) ◽  
pp. 1062-1067 ◽  
Author(s):  
Roland H. H. Van Balkom ◽  
Wen-Zhi Zhan ◽  
Y. S. Prakash ◽  
P. N. Richard Dekhuijzen ◽  
Gary C. Sieck
Keyword(s):  
Isometric Force ◽  
Contractile Properties ◽  
Diaphragm Muscle ◽  
Peak Power Output ◽  
Rat Diaphragm ◽  
Fiber Morphology ◽  
Shortening Velocity ◽  
Maximum Isometric Force ◽  
Induced Changes ◽  
Isotonic Contractions

Van Balkom, Roland H. H., Wen-Zhi Zhan, Y. S. Prakash, P. N. Richard Dekhuijzen, and Gary C. Sieck. Corticosteroid effects on isotonic contractile properties of rat diaphragm muscle. J. Appl. Physiol. 83(4): 1062–1067, 1997.—The effects of corticosteroids (CS) on diaphragm muscle (Diam) fiber morphology and contractile properties were evaluated in three groups of rats: controls (Ctl), surgical sham and weight-matched controls (Sham), and CS-treated (6 mg ⋅ kg−1 ⋅ day−1prednisolone at 2.5 ml/h for 3 wk). In the CS-treated Diam, there was a selective atrophy of type IIx and IIb fibers, compared with a generalized atrophy of all fibers in the Sham group. Maximum isometric force was reduced by 20% in the CS group compared with both Ctl and Sham. Maximum shortening velocity in the CS Diamwas slowed by ∼20% compared with Ctl and Sham. Peak power output of the CS Diam was only 60% of Ctl and 70% of Sham. Endurance to repeated isotonic contractions improved in the CS-treated Diam compared with Ctl. We conclude that the atrophy of type IIx and IIb fibers in the Diam can only partially account for the CS-induced changes in isotonic contractile properties. Other factors such as reduced myofibrillar density or altered cross-bridge cycling kinetics are also likely to contribute to the effects of CS treatment.

scholarly journals Skeletal muscle repair in a mouse model of nemaline myopathy

2006 ◽  
Vol 15 (17) ◽  
pp. 2603-2612 ◽  
Author(s):  
Despina Sanoudou ◽  
Mark A. Corbett ◽  
Mei Han ◽  
Majid Ghoddusi ◽  
Mai-Anh T. Nguyen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Nemaline Myopathy ◽  
Muscle Repair

scholarly journals Active shortening protects against stretch-induced force deficits in human skeletal muscle

2017 ◽  
Vol 122 (5) ◽  
pp. 1218-1226 ◽  
Author(s):  
Anjali L. Saripalli ◽  
Kristoffer B. Sugg ◽  
Christopher L. Mendias ◽  
Susan V. Brooks ◽  
Dennis R. Claflin
Keyword(s):  
Skeletal Muscle ◽  
High Velocity ◽  
Isometric Force ◽  
Human Subjects ◽  
Causative Factor ◽  
Negative Consequences ◽  
Shortening Velocity ◽  
Contracting Muscle ◽  
Working Hypothesis ◽  
Force Maintenance

Skeletal muscle contraction results from molecular interactions of myosin “crossbridges” with adjacent actin filament binding sites. The binding of myosin to actin can be “weak” or “strong,” and only strong binding states contribute to force production. During active shortening, the number of strongly bound crossbridges declines with increasing shortening velocity. Forcibly stretching a muscle that is actively shortening at high velocity results in no apparent negative consequences, whereas stretch of an isometrically (fixed-length) contracting muscle causes ultrastructural damage and a decline in force-generating capability. Our working hypothesis is that stretch-induced damage is uniquely attributable to the population of crossbridges that are strongly bound. We tested the hypothesis that stretch-induced force deficits decline as the prevailing shortening velocity is increased. Experiments were performed on permeabilized segments of individual skeletal muscle fibers obtained from human subjects. Fibers were maximally activated and allowed either to generate maximum isometric force (Fo), or to shorten at velocities that resulted in force maintenance of ≈50% Fo or ≈2% Fo. For each test condition, a rapid stretch equivalent to 0.1 × optimal fiber length was applied. Relative to prestretch Fo, force deficits resulting from stretches applied during force maintenance of 100, ≈50, and ≈2% Fo were 23.2 ± 8.6, 7.8 ± 4.2, and 0.3 ± 3.3%, respectively (means ± SD, n = 20). We conclude that stretch-induced damage declines with increasing shortening velocity, consistent with the working hypothesis that the fraction of strongly bound crossbridges is a causative factor in the susceptibility of skeletal muscle to stretch-induced damage. NEW & NOTEWORTHY Force deficits caused by stretch of contracting muscle are most severe when the stretch is applied during an isometric contraction, but prevented if the muscle is shortening at high velocity when the stretch occurs. This study indicates that velocity-controlled modulation of the number of strongly bound crossbridges is the basis for the observed relationship between stretch-induced muscle damage and prevailing shortening velocity.

scholarly journals Causes of fatigue in slow-twitch rat skeletal muscle during dynamic activity

2009 ◽  
Vol 297 (3) ◽  
pp. R900-R910 ◽  
Author(s):  
Morten Munkvik ◽  
Per Kristian Lunde ◽  
Ole M. Sejersted
Keyword(s):  
Skeletal Muscle ◽  
Isometric Force ◽  
Force Production ◽  
Maximum Force ◽  
Stimulation Protocol ◽  
Shortening Velocity ◽  
Dynamic Activity ◽  
Initial Values ◽  
Isotonic Shortening

Skeletal muscle fatigue is most often studied in vitro at room temperature and is classically defined as a decline in maximum force production or power output, exclusively linked to repeated isometric contractions. However, most muscles shorten during normal use, and we propose that both the functional correlate of fatigue, as well as the fatigue mechanism, will be different during dynamic contractions compared with static contractions. Under isoflurane anesthesia, fatigue was induced in rat soleus muscles in situ by isotonic shortening contractions at 37°C. Muscles were stimulated repeatedly for 1 s at 30 Hz every 2 s for a total of 15 min. The muscles were allowed to shorten isotonically against a load corresponding to one-third of maximal isometric force. Maximal unloaded shortening velocity (V0), maximum force production (Fmax), and isometric relaxation rate (−dF/d t) was reduced after 100 s but returned to almost initial values at the end of the stimulation protocol. Likewise, ATP and creatine phosphate (CrP) were reduced after 100 s, but the level of CrP was partially restored to initial values after 15 min. The rate of isometric force development, the velocity of shortening, and isotonic shortening were also reduced at 100 s, but in striking contrast, did not recover during the remainder of the stimulation protocol. The regulatory myosin light chain (MLC2s) was dephosphorylated after 100 s and did not recover. Although metabolic changes may account for the changes of Fmax, −dF/d t, and V0, dephosphorylation of MLC2s may be involved in the fatigue seen as sustained slower contraction velocities and decreased muscle shortening.

scholarly journals High ionic strength and low pH detain activated skinned rabbit skeletal muscle crossbridges in a low force state.

1993 ◽  
Vol 101 (4) ◽  
pp. 487-511 ◽  
Author(s):  
C Y Seow ◽  
L E Ford
Keyword(s):  
Skeletal Muscle ◽  
Ionic Strength ◽  
Isometric Force ◽  
Maximum Velocity ◽  
Low Ph ◽  
High Ionic Strength ◽  
Rabbit Skeletal Muscle ◽  
Shortening Velocity ◽  
Force Ratio ◽  
Force Difference

The effects of varying pH and ionic strength on the force-velocity relations and tension transients of skinned rabbit skeletal muscle were studied at 1-2 degrees C. Both decreasing pH from 7.35 to 6.35 and raising ionic strength from 125 to 360 mM reduced isometric force by about half and decreased sarcomere stiffness by about one-fourth, so that the stiffness/force ratio was increased by half. Lowering pH also decreased maximum shortening velocity by approximately 29%, while increasing ionic strength had little effect on velocity. These effects on velocity were correlated with asymmetrical effects on stiffness. The increase in the stiffness/force ratio with both interventions was manifest as a greater relative force change associated with a sarcomere length step. This force difference persisted for a variable time after the step. At the high ionic strength the force difference was long-lasting after stretches but relaxed quickly after releases, suggesting that the structures responsible would not impose much resistance to steady-state shortening. The opposite was found in the low pH experiments. The force difference relaxed quickly after stretches but persisted for a long time after releases. Furthermore, this force difference reached a constant value of approximately 8% of isometric force with intermediate sizes of release, and was not increased with larger releases. This value was almost identical to the value of an internal load that would be sufficient to account for the reduction in maximum velocity seen at the low pH. The results are interpreted as showing that both low pH and high ionic strength inhibit the movement of crossbridges into the force-generating parts of their cycle after they have attached to the actin filaments, with very few other effects on the cycle. The two interventions are different, however, in that detained bridges can be detached readily by shortening when the detention is caused by high ionic strength but not when it is caused by low pH.

scholarly journals Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96921 ◽  
Author(s):  
Darren T. Hwee ◽  
Adam Kennedy ◽  
Julie Ryans ◽  
Alan J. Russell ◽  
Zhiheng Jia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Muscle Function ◽  
Fast Skeletal Muscle ◽  
And Performance
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