ORCID Profile
0000-0002-4400-0817
Current Organisation
University of Western Australia
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Publisher: Elsevier BV
Date: 10-2012
Publisher: Wiley
Date: 24-07-2015
DOI: 10.1111/APHA.12547
Publisher: MIT Press - Journals
Date: 04-2015
DOI: 10.1162/LEON_A_00976
Abstract: During normal daily activities, muscles are required to lengthen as frequently as they shorten to produce movement. Lengthening muscle actions are associated with high forces and low energy consumption, but can often result in muscle injury. These unique features are not explained adequately by current (cross-bridge) theories of muscle contraction. Using specific myosin inhibitors and different temperatures the author has examined the molecular mechanisms of stretch-induced force enhancement. The results, which suggest that lengthening force arises from the strain of both cross-bridge and non-cross-bridge components of the sarcomere, help to refine understanding of the molecular mechanisms of muscle contraction.
Publisher: Wiley
Date: 07-06-2006
Publisher: Public Library of Science (PLoS)
Date: 08-01-2012
Publisher: Springer Science and Business Media LLC
Date: 04-2005
DOI: 10.1007/S10974-005-4568-0
Abstract: We examined the tension responses induced by rapid temperature-jumps (T-jumps) applied at different times during twitch and tetanic contractions in small intact fibre bundles (5-10 fibres) isolated from a fast foot muscle (flexor hallucis brevis) of the rat. A rapid T-jump of 2-4 degrees C was induced by a 0.2 ms infrared (lambda = 1.32 microm) laser pulse applied to the fibre bundle immersed in a 50 microl trough of physiological saline, the temperature of which was cl ed at different steady temperatures ranging from 10 to 30 degrees C. In a tetanic contraction, the tension increased to the same steady level when a standard T-jump was applied at different intervals after the onset of stimulation thus, with maximal activation, an enhanced force generation by T-jump leads to a new steady state. In a twitch contraction, a T-jump induced a large, potentiation of tension when it was applied during the rising phase. Whereas the twitch relaxation subsequent to a T-jump was faster in all cases, the litude of the twitch tension potentiation decreased as the T-jump was delayed with respect to the stimulus, and there was no increase of tension when a T-jump was placed on the relaxation phase of the twitch. The increase of tension induced by a T-jump applied on the rising phase resulted in peak tension that was greater than the tension in control twitches at the steady post-T-jump temperature therefore tension was higher than that expected on the basis of steady state temperature dependence of twitch tension. Whether these effects on a twitch contraction arise from differential fibre-heating by a T-jump that leads to shortening and development of sarcomere length disorder etc remain unclear. However, the findings may be interpreted as indicating that twitch tension increment by a T-jump occurs when excitation (the action potential) leading to calcium release and thin filament activation occur at the low temperature, whereas the crossbridge force-generation processes (and Ca2+-uptake) proceed at the higher temperature.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.NMD.2010.09.013
Abstract: This study evaluated the contribution of the pro-inflammatory cytokine, tumour necrosis factor (TNF) to the severity of exercise-induced muscle damage and subsequent myofibre necrosis in mdx mice. Adult mdx and non-dystrophic C57 mice were treated with the mouse-specific TNF antibody cV1q before undergoing a damaging eccentric contraction protocol performed in vivo on a custom built mouse dynamometer. Muscle damage was quantified by (i) contractile dysfunction (initial torque deficit) immediately after the protocol, (ii) subsequent myofibre necrosis 48 h later. Blockade of TNF using cV1q significantly reduced contractile dysfunction in mdx and C57 mice compared with mice injected with the negative control antibody (cVaM) and un-treated mice. Furthermore, cV1q treatment significantly reduced myofibre necrosis in mdx mice. This in vivo evidence that cV1q reduces the TNF-mediated adverse response to exercise-induced muscle damage supports the use of targeted anti-TNF treatments to reduce the severity of the functional deficit and dystropathology in DMD.
Publisher: Wiley
Date: 30-09-2017
DOI: 10.1113/JP274229
Publisher: Wiley
Date: 22-12-2005
DOI: 10.1111/J.1748-1716.2005.01499.X
Abstract: This study determined whether fatigue in skeletal muscle is primarily due to the repeated elevations of myoplasmic free calcium concentration ([Ca(2+)](i)) or to metabolite accumulation. We examined the effects of N-benzyl-p-toluene sulphonamide (BTS) which is a potent and specific inhibitor of fast muscle myosin-II on the development of fatigue in mouse flexor digitorum brevis (FDB) muscle fibres. Single intact FDB fibres were micro-injected with indo-1 to monitor changes in [Ca(2+)](i) and stimulated repeatedly for a maximum of 150 tetani or until force declined to 40%. BTS markedly reduced tetanic force but had no effect on the tetanic [Ca(2+)](i) transients. When fatigue was induced in the presence of BTS, the reduction in [Ca(2+)](i) and force transients occurred much more slowly than in the absence of BTS. The extent of force depression was similar after induction of fatigue in fibres exposed to Tyrode only or to BTS and force recovered to the same extent. The results suggest that the decrease in tetanic [Ca(2+)](i) and force caused during fatigue are due mainly to accumulated metabolic changes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2000
DOI: 10.1097/00005768-200003000-00015
Abstract: The purpose of this study was to determine the effects of hamstring fatigue induced by repeated maximal efforts on hamstring muscle function during maximal sprint running. Twelve subjects performed three maximal 40-m sprints during which time high-speed film of the subjects' sprint action and EMG of five lower extremity muscles were recorded (nonfatigued condition, NFC). Subjects then performed specific and general hamstring fatigue tasks followed by three final 40-m sprints (fatigued condition, FC) during which time high-speed film and EMG of the same muscles were again recorded. Statistical analysis of the kinematic data indicated the following significant (P < 0.05) changes in the subjects' running action from the NFC to the FC: decreased hip and knee flexion at maximum knee extension in the swing phase of the sprint cycle, decreased leg angular velocity immediately before foot-ground contact (FGC), and decreased angular displacement of the trunk, thigh, and leg segments during the late swing phase. Statistical analysis of the EMG data indicated a significant increase in the duration of hamstring activity and earlier cessation of rectus femoris activity during the swing phase of the sprint stride. It was concluded that these changes in the kinematic and EMG parameters of sprint running primarily served as protective mechanisms to reduce stress placed on the hamstring muscles at critical phases of the stride cycle.
Publisher: Public Library of Science (PLoS)
Date: 28-03-2014
Publisher: The Company of Biologists
Date: 2012
DOI: 10.1242/JEB.070466
Abstract: The region over which skeletal muscles operate on their force-length (F-L) relationship is fundamental to the mechanics, control and economy of movement. Yet, surprisingly little experimental data exist on normalized length operating ranges of muscle during human gait, or how they are modulated when mechanical demands (such as force output) change. Here we explore the soleus muscle (SOL) operating lengths experimentally in a group of healthy young adults by combining subject-specific F-L relationships with in vivo muscle imaging during gait. We test whether modulation of operating lengths occurs between walking and running, two gaits that require different levels of force production and different muscle-tendon mechanics, and examine the relationship between optimal fascicle lengths (L0) and normalized operating lengths during these gaits. We found that the mean active muscle lengths reside predominantly on the ascending limbs of the F-L relationship in both gaits (0.70 - 0.94 L0, walk 0.65 - 0.99 L0, run). Furthermore, the mean normalized muscle length at the time of the muscle's peak activation was the same between the two gaits (0.88 L0). The active operating lengths were conserved, despite a fundamentally different fascicle strain pattern between walking (stretch-shorten cycle) and running (near continuous shortening). Taken together, these findings indicate that the SOL operating length is highly conserved despite gait-dependant differences in muscle-tendon dynamics, and appear to be preferentially selected for stable force production compared to optimal force output (although length-dependent force capacity is high when maximal forces are expected to occur). In iduals with shorter L0 undergo smaller absolute muscle excursions (p& .05) so that the normalized length changes during walking and running remain independent of L0. The correlation between L0 and absolute length change was not explained on the basis of muscle moment arms or joint excursion, suggesting that regulation of muscle strain may occur via tendon stretch.
Publisher: Wiley
Date: 20-08-2012
DOI: 10.1002/MUS.23318
Abstract: The skeletal muscle weakness associated with many chronic diseases has been attributed to the catabolic effect of pro-inflammatory cytokines. We aimed to determine if local muscle inflammation has direct affects on contractile function and contributes to muscle weakness independent of muscle atrophy or mechanical injury. Local muscle inflammation was induced by injecting an algal-derived polysaccharide, carrageenan (10 mg/kg), into the right tibialis anterior muscle in healthy ARC mice. The contralateral muscle was injected with sterile isotonic saline, and the muscles were removed after 24 h for measurement of contractile function and cytokine concentration. Carrageenan significantly reduced maximum specific force, decreased the maximum rate of force development, altered the force-frequency relationship, and increased intramuscular levels of pro-inflammatory cytokines and chemokines. These results indicate that carrageenan directly affects contractile function and causes skeletal muscle weakness. Local muscle inflammation may contribute to the weakness observed in inflammatory related disorders.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2015
Publisher: Elsevier BV
Date: 10-2012
Publisher: Elsevier BV
Date: 10-2012
Publisher: MDPI AG
Date: 21-12-2022
DOI: 10.3390/IJMS24010076
Abstract: Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by a genetic deficiency of the membrane-associated protein dysferlin, which usually manifest post-growth in young adults. The disease is characterized by progressive skeletal muscle wasting in the limb-girdle and limbs, inflammation, accumulation of lipid droplets in slow-twitch myofibers and, in later stages, replacement of muscles by adipose tissue. Previously we reported myofiber-type specific differences in muscle contractile function of 10-month-old dysferlin-deficient BLAJ mice that could not be fully accounted for by altered myofiber-type composition. In order to further investigate these findings, we examined the impact of dysferlin deficiency on the abundance of calcium (Ca2+) handling and glucose/glycogen metabolism-related proteins in predominantly slow-twitch, oxidative soleus and fast-twitch, glycolytic extensor digitorum longus (EDL) muscles of 10-month-old wild-type (WT) C57BL/6J and dysferlin-deficient BLAJ male mice. Additionally, we compared the Ca2+ activation properties of isolated slow- and fast-twitch myofibers from 3-month-old WT and BLAJ male mice. Differences were observed for some Ca2+ handling and glucose/glycogen metabolism-related protein levels between BLAJ soleus and EDL muscles (compared with WT) that may contribute to the previously reported differences in function in these BLAJ muscles. Dysferlin deficiency did not impact glycogen content of whole muscles nor Ca2+ activation of the myofilaments, although soleus muscle from 10-month-old BLAJ mice had more glycogen than EDL muscles. These results demonstrate a further impact of dysferlin deficiency on proteins associated with excitation-contraction coupling and glycogen metabolism in skeletal muscles, potentially contributing to altered contractile function in dysferlinopathy.
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/JAPPLPHYSIOL.00565.2006
Abstract: Stretch of an activated muscle causes a transient increase in force during the stretch and a sustained, residual force enhancement (RFE) after the stretch. The purpose of this study was to determine whether RFE is present in human muscles under physiologically relevant conditions (i.e., when stretches were applied within the working range of large postural leg muscles and under submaximal voluntary activation). Submaximal voluntary plantar flexion (PF v ) and dorsiflexion (DF v ) activation was maintained by providing direct visual feedback of the EMG from soleus or tibialis anterior, respectively. RFE was also examined during electrical stimulation of the plantar flexion muscles (PF s ). Constant-velocity stretches (15°/s) were applied through a range of motion of 15° using a custom-built ankle torque motor. The muscles remained active throughout the stretch and for at least 10 s after the stretch. In all three activation conditions, the stable joint torque measured 9–10 s after the stretch was greater than the isometric joint torque at the final joint angle. When expressed as a percentage of the isometric torque, RFE values were 7, 13, and 12% for PF v , PF s , DF v , respectively. These findings indicate that RFE is a characteristic of human skeletal muscle and can be observed during submaximal (25%) voluntary activation when stretches are applied on the ascending limb of the force-length curve. Although the underlying mechanisms are unclear, it appears that sarcomere popping and passive force enhancement are insufficient to explain the presence of RFE in these experiments.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2003
DOI: 10.1007/S00421-003-0893-4
Abstract: In experiments on isolated animal muscle, the force produced during active lengthening contractions can be up to twice the isometric force, whereas in human experiments lengthening force shows only modest, if any, increase in force. The presence of synergist and antagonist muscle activation associated with human experiments in situ may partly account for the difference between animal and human studies. Therefore, this study aimed to quantify the force-velocity relationship of the human soleus muscle and assess the likelihood that co-activation of antagonist muscles was responsible for the inhibition of torque during submaximal voluntary plantar flexor efforts. Seven subjects performed submaximal voluntary lengthening, shortening(at angular, velocities of +5, -5, +15, -15 and +30, and -30 degrees s(-1)) and isometric plantar flexor efforts against an ankle torque motor. Angle-specific (90 degrees ) measures of plantar flexor torque plus surface and intramuscular electromyography from soleus, medial gastrocnemius and tibialis anterior were made. The level of activation (30% of maximal voluntary isometric effort) was maintained by providing direct visual feedback of the soleus electromyogram to the subject. In an attempt to isolate the contribution of soleus to the resultant plantar flexion torque, activation of the synergist and antagonist muscles were minimised by: (1) flexing the knee of the test limb, thereby minimising the activation of gastrocnemius, and (2) applying an anaesthetic block to the common peroneal nerve to eliminate activation of the primary antagonist muscle, tibialis anterior and the synergist muscles, peroneus longus and peroneus brevis. Plantar flexion torque decreased significantly ( P<0.05) after blocking the common peroneal nerve which was likely due to abolishing activation of the peroneal muscles which are synergists for plantar flexion. When normalised to the corresponding isometric value, the force-velocity relationship between pre- and post-block conditions was not different. In both conditions, plantar flexion torques during shortening actions were significantly less than the isometric torque and decreased at faster velocities. During lengthening actions, however, plantar flexion torques were not significantly different from isometric regardless of angular velocity. It was concluded that the apparent inhibition of lengthening torques during voluntary activation is not due to co-activation of antagonist muscles. Results are presented as mean (SEM).
Publisher: Springer Science and Business Media LLC
Date: 16-06-2012
DOI: 10.1007/S10974-012-9307-8
Abstract: The aim of the present study was to examine the temperature dependence of active force in lengthening and shortening muscle. Experiments were done, in vitro, on bundles of intact fibres (fibre length L(0) ~2 mm sarcomere length ~2.5 μm) isolated from a rat fast muscle (flexor hallucis brevis) and a r length change of 5-7% L(0) was applied on the plateau of an isometric tetanic contraction. R lengthening increased and r shortening decreased the muscle tension to new approximately steady levels in a velocity-dependent way. The isometric tension and the lower steady tension reached at a given shortening velocity, increased with warming from 10 to 35 °C and the relation between tension and reciprocal absolute temperature was sigmoidal. However, the tension-temperature curve of shortening muscle was sharper and shifted to higher temperature with increased velocity. In contrast, the enhanced steady tension during lengthening at a given velocity was largely temperature-insensitive within the same temperature range we hypothesize that the tension-temperature curve may be shifted to lower temperatures in lengthening muscle. Consequently, when normalised to the isometric tension at each temperature, the tension during lengthening at a given velocity decreased exponentially with increase of temperature. The residual force enhancement that remains after r lengthening showed a similar behaviour and was markedly reduced in warming from 10 to 35 °C. The findings are consistent with the thesis that active force generation in muscle is endothermic and strain-sensitive during shortening with a faster crossbridge cycle it becomes more pronounced, but during lengthening it becomes depressed as the cycle slows in a velocity-dependent way. The residual force enhancement may be caused by the same process in addition to non-crossbridge mechanism(s).
Publisher: Wiley
Date: 19-01-2018
DOI: 10.1113/JP275662
Publisher: American Thoracic Society
Date: 11-2013
Publisher: Wiley
Date: 08-2001
DOI: 10.1111/J.1469-7793.2001.00913.X
Abstract: 1. The present study investigated the effects of lengthening and shortening actions on H-reflex litude. H-reflexes were evoked in the soleus (SOL) and medial gastrocnemius (MG) of human subjects during passive isometric, lengthening and shortening actions performed at angular velocities of 0, +/-2, +/-5 and +/-15 deg s(-1). 2. H-reflex litudes in both SOL and MG were significantly depressed during passive lengthening actions and facilitated during passive shortening actions, when compared with the isometric H-reflex litude. 3. Four experiments were performed in which the latencies from the onset of movement to delivery of the stimulus were altered. Passive H-reflex modulation during lengthening actions was found to begin at latencies of less than 60 ms suggesting that this inhibition was due to peripheral and/or spinal mechanisms. 4. It is postulated that the H-reflex modulation seen in the present study is related to the tonic discharge of muscle spindle afferents and the consequent effects of transmission within the Ia pathway. Inhibition of the H-reflex at less than 60 ms after the onset of muscle lengthening may be attributed to several mechanisms, which cannot be distinguished using the current protocol. These may include the inability to evoke volleys in Ia fibres that are refractory following muscle spindle discharge during rapid muscle lengthening, a reduced probability of transmitter release from the presynaptic terminal (homosynaptic post-activation depression) and presynaptic inhibition of Ia afferents from plantar flexor agonists. Short latency facilitation of the H-reflex may be attributed to temporal summation of excitatory postsynaptic potentials arising from muscle spindle afferents during rapid muscle lengthening. At longer latencies, presynaptic inhibition of Ia afferents cannot be excluded as a potential inhibitory mechanism.
Publisher: Wiley
Date: 14-11-2007
Publisher: Wiley
Date: 18-09-2019
DOI: 10.1002/PPUL.24519
Abstract: In utero diaphragm development is critically important for postnatal respiratory function and any disturbance to fetal development may lead to diaphragm dysfunction and respiratory complications in the postnatal period. Intrauterine growth restriction (IUGR) has been shown to affect respiratory function in a sex-dependent manner however, the effect of IUGR on diaphragm function is unknown. This study used a maternal hypoxia-induced mouse model of IUGR to investigate the impact of IUGR on diaphragm function and structure in male and female adult offspring. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O IUGR offspring were lighter at birth and remained lighter at 8 weeks of age compared to Controls. While diaphragm force (maximal or twitch) was not affected by treatment or sex, the IUGR group exhibited a longer half-relaxation time after twitch contractions compared to Control. Female offspring had a lower maximum rate of force development and higher fatigue resistance compared to males, independent of IUGR. There was no difference in the diaphragm myofibre cross-sectional area between groups or sexes. Sex and IUGR independently affect diaphragm contraction in adult mice without changes in structure. This study demonstrates that IUGR affects diaphragm contractile function in later life and could impair respiratory function if exacerbated under conditions of increased respiratory load.
Publisher: Public Library of Science (PLoS)
Date: 02-11-2017
Publisher: Wiley
Date: 18-01-2016
DOI: 10.1113/JP271418
Publisher: Wiley
Date: 21-10-2023
DOI: 10.1113/JP285263
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: In the present study we investigated tension regulation in the human soleus (SOL) muscle during controlled lengthening and shortening actions. Eleven subjects performed plantar flexor efforts on an ankle torque motor through 30 degrees of ankle displacement (75 degrees -105 degrees internal ankle angle) at lengthening and shortening velocities of 5, 15 and 30 degrees. S(-1). To isolate the SOL from the remainder of the triceps surae, the subject's knee was flexed to 60 degrees during all trials. Voluntary plantar flexor efforts were performed under two test conditions: (1) maximal voluntary activation (MVA) of the SOL, and (2) constant submaximal voluntary activation (SVA) of the SOL. SVA trials were performed with direct visual feedback of the SOL electromyogram (EMG) at a level resulting in a torque output of 30% of isometric maximum. Angle-specific (90 degrees ankle angle) torque and EMG of the SOL, medial gastrocnemius (MG) and tibialis anterior (TA) were recorded. In seven subjects from the initial group, the test protocol was repeated under submaximal percutaneous electrical activation (SEA) of SOL (to 30% isometric maximal effort). Lengthening torques were significantly greater than shortening torques in all test conditions. Lengthening torques in MVA and SVA were independent of velocity and remained at the isometric level, whereas SEA torques were greater than isometric torques and increased at higher lengthening velocities. Shortening torques were lower than the isometric level for all conditions. However, whereas SVA and SEA torques decreased at higher velocities of shortening, MVA torques were independent of velocity. These results indicate velocity- and activation-type-specific tension regulation in the human SOL muscle.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2008
DOI: 10.1007/S00424-008-0568-4
Abstract: Duchenne muscular dystrophy (DMD) is a genetic disorder in which muscle weakness and fragility contribute to ongoing muscle degeneration. Although exercise-induced muscle damage is associated with adaptation that protects normal muscle from further damage, exploiting this process to protect dystrophic muscle has been avoided for fear of inducing excessive muscle degeneration. However, muscle-specific over-expression of the class 1:Ea isoform of insulin-like growth factor-1 (IGF-1) reduces myofibre necrosis in dystrophic mdx mice (a model for DMD) and, therefore, may enhance the adaptation process in response to eccentric exercise. To test this hypothesis, we evaluated the effect of transgenic class 1:Ea IGF-1 over-expression on the susceptibility to muscle damage and subsequent adaptation in 12-week-old dystrophic mdx and non-dystrophic control mice. Experiments were conducted in vivo using a custom-built isokinetic mouse dynamometer to measure the deficit in joint torque (indicating muscle damage) after 20 maximal lengthening (eccentric) contractions. Adaptation to this damaging exercise was evaluated by repeating the protocol 7 days after the initial exercise. The over-expression of IGF-1 significantly increased the normalised joint torque in non-dystrophic mice and appeared to ameliorate the muscle weakness in dystrophic mice. All mice displayed a marked reduction in the susceptibility to muscle damage on day 7 however, this adaptation was unaffected by IGF-1, showing that IGF-1 does not protect the dystrophic muscles of adult mdx mice against damage resulting from maximal lengthening contractions.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Springer Science and Business Media LLC
Date: 04-2005
DOI: 10.1007/S10974-005-2679-2
Abstract: We have examined the effects of N-benzyl-p-toluene sulphonamide (BTS), a potent and specific inhibitor of fast muscle myosin-II, using small bundles of intact fibres or single fibres from rat foot muscle. BTS decreased tetanic tension reversibly in a concentration-dependent manner with half-maximal inhibition at approximately approximately 2 microM at 20 degrees C. The inhibition of tension with 10 microM BTS was marked at the three temperatures examined (10, 20 and 30 degrees C), but greatest at 10 degrees C. BTS decreased active muscle stiffness to a lesser extent than tetanic tension indicating that not all of the tension inhibition was due to a reduced number of attached cross-bridges. BTS-induced inhibition of active tension was not accompanied by any change in the free myoplasmic Ca2+ transients. The potency and specificity of BTS make it a very suitable myosin inhibitor for intact mammalian fast muscle and should be a useful tool for the examination of outstanding questions in muscle contraction.
Publisher: Wiley
Date: 21-10-2010
DOI: 10.1002/MUS.21744
Abstract: When an active muscle is stretched, the force increases due to strain of contractile and noncontractile proteins. We examined this force enhancement in rat extensor digitorum longus (EDL) and soleus muscles, which differ in their composition of these proteins, and their susceptibility to damage. Small stretches were applied at different velocities during isometric contractions from which we quantified the velocity-dependent contractile and velocity-independent noncontractile contributions to force enhancement. Whereas the contractile contribution was significantly greater in soleus than EDL, the noncontractile force enhancement was significantly greater in EDL than soleus, and increased ≈6-fold after damaging eccentric contractions. The increased contractile stiffness may be functionally beneficial in slow muscle, as resistance to lengthening is fundamental to maintaining posture. Following stretch-induced muscle damage this capacity is compromised, leading to increased strain of noncontractile proteins that may facilitate the activation of signaling pathways involved in muscle adaptation to injury.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2019
Publisher: Wiley
Date: 30-10-2014
DOI: 10.1002/MUS.24256
Abstract: Protease-activated receptors (PARs) may play a role in skeletal muscle development. We compared the contractile properties of slow-twitch soleus muscles and fast-twitch extensor digitorum longus (EDL) muscles from PAR-1 null and littermate control mice. Contractile function was measured using a force transducer system. Fiber type proportions were determined using immunohistochemistry. Soleus muscles from PAR-1 null mice exhibited longer contraction times, a leftward shift in the force-stimulation frequency relationship, and decreased fatiguability compared with controls. PAR-1 null soleus muscles also had increased type 1 and decreased type IIb/x fiber numbers compared with controls. In PAR-1 null EDL muscles, no differences were found, except for a slower rate of fatigue compared with controls. The absence of PAR-1 results in a slower skeletal muscle contractile phenotype, likely due to an increase in type I and a decrease in type IIb/x fiber numbers. Muscle Nerve 50: 991-998, 2014.
Publisher: Rockefeller University Press
Date: 12-11-2022
Abstract: Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disease characterized by progressive loss of skeletal muscle. The mechanisms underlying the DMD pathology likely involve the complex interaction between reactive oxygen species (ROS) impaired Ca2+ handling and chronic inflammation, characterized by the presence of immune cells such as neutrophils. Hypochlorous acid (HOCl) is a highly reactive form of ROS produced endogenously via the actions of myeloperoxidase, an enzyme secreted by neutrophils. Myeloperoxidase activity is significantly elevated in dystrophic muscle. This study aimed to determine the effect of HOCl exposure on excitation–contraction coupling and its potential contribution to the dystrophic pathology. Isolated extensor digitorum longus (EDL) muscles and single fibers from C57 (wild type) and mdx (dystrophic) mice were used to investigate the effects of HOCl on whole muscle function, intracellular Ca2+ handling, and myofilament force production. HOCl exposure significantly decreased maximum specific force in isolated EDL muscles by 26% and 49%, respectively, in C57 and mdx mice (P & 0.0001). In single interosseous fibers, HOCl exposure significantly increased resting intracellular Ca2+ concentration by ∼17–19% (P & 0.05) and decreased the litude of electrically induced Ca2+ transients by ∼45% and 50%, respectively, in C57 and mdx fibers (C57, P & 0.05 mdx, P & 0.01). These effects of HOCl on resting Ca2+ could be blocked via application of tetracaine (ryanodine receptor blocker) or Gd3+ (stretch-activated channel blocker C57, P & 0.01 mdx, P & 0.01 for both). The effect of HOCl on Ca2+ transient litude was significantly reduced by Gd3+ (C57, P & 0.05 mdx, P & 0.01). In chemically skinned EDL fibers, HOCl exposure decreased maximum Ca2+-activated force by ∼40% in both C57 and mdx fibers (P & 0.001). These results indicate that HOCl potently affects excitation–contraction coupling via impaired Ca2+ handling and myofilament force production. Hence, HOCl potentially links the chronic inflammation, oxidative stress, and impaired Ca2+ handling that underlies the dystrophic pathology.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/PR.2017.99
Abstract: BackgroundPregnant women at a high risk of preterm delivery receive glucocorticoids to accelerate fetal lung maturation and surfactant synthesis. However, the effect of antenatal steroids on the developing diaphragm remains unclear. We hypothesized that maternal betamethasone impairs the fetal diaphragm, and the magnitude of the detrimental effect increases with longer duration of exposure. We aimed to determine how different durations of fetal exposure to maternal betamethasone treatment influence the fetal diaphragm at the functional and molecular levels.MethodsDate-mated merino ewes received intramuscular injections of saline (control) or two doses of betamethasone (5.7 mg) at an interval of 24 h commencing either 2 or 14 days before delivery. Preterm lambs were killed after cesarean delivery at 121-day gestational age. In vitro contractile measurements were performed on the right hemidiaphragm, whereas molecular/cellular analyses used the left costal diaphragm.ResultsDifferent durations of fetal exposure to maternal betamethasone had no consistent effect on the protein metabolic pathway, expression of glucocorticoid receptor and its target genes, cellular oxidative status, or contractile properties of the fetal lamb diaphragm.ConclusionThese data suggest that the potential benefits of betamethasone exposure on preterm respiratory function are not compromised by impaired diaphragm function after low-dose maternal intramuscular glucocorticoid exposure.
Publisher: Elsevier BV
Date: 10-2017
Publisher: American Physiological Society
Date: 04-2018
DOI: 10.1152/AJPREGU.00150.2017
Abstract: The preterm diaphragm is functionally immature compared with its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation-induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10 mg lipopolysaccharide (LPS) 2 or 7 days before delivery at 121 days (preterm) or ∼145 days (term) of gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines, diaphragm myosin heavy chain (MHC) isoforms, and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs ( P 0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2-day LPS exposure was significantly lower than in controls (by ~20%, P 0.05). In preterm lambs, maximum forces after 2-day and 7-day LPS exposures were significantly lower than in controls (by ~30%, P 0.05). Peak twitch force after LPS exposure was significantly lower in preterm than in controls, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times, and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7-day versus 2-day LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.
Publisher: Wiley
Date: 08-02-2013
DOI: 10.1002/PPUL.22762
Abstract: The preterm diaphragm is structurally and functionally immature, potentially contributing to an increased risk of respiratory distress and failure. We investigated developmental changes in contractile function and susceptibility to fatigue of the costal diaphragm in the fetal lamb to understand factors contributing to the risk of developing diaphragm dysfunction and respiratory disorders. We hypothesized that the functional capacity of the diaphragm will vary with maturational stage as will its susceptibility to fatigue. Lambs were studied at 75, 100, 125, 145, 154, 168, and 200 days postconceptional age (term = 147 days). Lambs were euthanized (sodium pentobarbitone, 100 mg/kg) either at delivery or immediately prior to post-mortem for postnatal lambs. Contractile function was assessed on longitudinal strips of intact muscle fibers and the remaining tissue frozen in liquid nitrogen for analysis of myosin heavy chain (MHC) mRNA expression and protein content. Fetal development of diaphragm function was characterized by a significant increase in maximum specific force, increased susceptibility to fatigue, reduced twitch contraction times, and a progressive increase in MHCI and MHCII protein content. Postnatally, there was a progressive decrease in the susceptibility to fatigue that coincided with an increase in the MHC I:II protein ratio. These data indicate that the functional capacity of the diaphragm varies with maturational age and may be an important determinant of the susceptibility to preterm respiratory failure.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2004
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 30-08-2005
Publisher: Wiley
Date: 26-08-2015
DOI: 10.1111/RESP.12615
Abstract: In utero infection may critically influence diaphragm development and predispose preterm infants to postnatal respiratory failure. We aimed to determine how frequency and gestational age (GA) at time of intra-amniotic (IA) lipopolysaccharide (LPS) exposure affects preterm diaphragm function. Pregnant ewes received IA injections of saline or 10-mg LPS at 7 days or 21 days or weekly injections 21, 14 and 7 days before delivery at 121-day GA. Foetal lambs were killed with pentobarbitone (150 mg/kg intravenous). Diaphragm contractile function was measured in vitro. Muscle fibre type, activation of protein synthesis and degradation pathways, pro-inflammatory signalling and oxidative stress were evaluated using immunofluorescence staining, RT-qPCR, ELISA, Western blotting and biochemical assay. In utero LPS exposure significantly impaired diaphragm contractile function. LPS exposure 7 days before delivery caused maximum specific twitch and tetanic forces 30% lower than controls. When the initial LPS exposure occurred 21 days before delivery maximum specific forces were 40% lower than controls. Earlier LPS exposure also prolonged twitch contraction time, increased fatigue resistance and elevated protein carbonyl content. Despite increased white blood cell counts and interleukin-6 mRNA expression following weekly LPS exposure, there were no significant differences in contractile properties between exposure 21 days before delivery and repeated LPS groups suggesting that frequency of inflammatory exposure does not influence the severity of contractile dysfunction. GA at time of initial LPS exposure, rather than frequency of exposure, determines the extent of inflammation-induced diaphragm dysfunction.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 10-2012
Publisher: Wiley
Date: 12-2012
Publisher: Elsevier BV
Date: 12-2022
Publisher: Springer New York
Date: 2010
DOI: 10.1007/978-1-4419-6366-6_12
Abstract: Analysis of tension responses to r length changes in muscle can provide important information about the crossbridge cycle. During a r length change, the force response of an active muscle shows an early change in slope (the P₁ transition) followed by a later, gradual change in slope (the P₂ transition). Modeling shows that the first transition reflects the tension change associated with the crossbridge power stroke in shortening and with its reversal in lengthening the reduction in slope at the second transition occurs when most of the crossbridges (myosin heads) that were attached at the start of the r become detached the steady tension during shortening is borne mainly by post-stroke heads whereas tension during lengthening is borne mostly by pre-stroke heads. After the P₂ transition, the tension reaches a steady level in the model whereas in the experiments the tension continues to increase during lengthening or to decrease during shortening this tension change is seen at a wide range of sarcomere lengths and even when active force is reduced by a myosin inhibitor. It appears that some non-crossbridge components in muscle fibers stiffen upon activation and contribute to the continued tension rise during lengthening release of such tension leads to tension decline during shortening. Thus, non-crossbridge visco-elasticity in sarcomeres may also contribute to energy storage and release during in situ muscle function.
No related grants have been discovered for Gavin Pinniger.