%0 Journal Article
%~ PubMed
%A Ju, Yue-Kun
%A Woodcock, Elizabeth A
%A Allen, David G
%A Cannell, Mark B
%T Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms.
%B Journal of Molecular and Cellular Cardiology
%D 2012
%C United Kingdom
%I Academic Press
%V 53
%N 3
%P 375-381
%@ 1095-8584
%X Intracellular Ca(2+) plays an important role in the control of the heart rate through the interaction between Ca(2+) release by ryanodine receptors in the sarcoplasmic reticulum (SR) and the extrusion of Ca(2+) by the sodium-calcium exchanger which generates an inward current. A second type of SR Ca(2+) release channel, the inositol 1,4,5-trisphosphate receptor (IP(3)R), can release Ca(2+) from SR stores in many cell types, including cardiac myocytes. However, it is still uncertain whether IP(3)Rs play any functional role in regulating the heart rate. Accumulated evidence shows that IP(3) and IP(3)R are involved in rhythm control in non-cardiac pacemaker tissues and in the embryonic heart. In this review we focus on intracellular Ca(2+) oscillations generated by Ca(2+) release from IP(3)R that initiates membrane depolarisation and provides a common mechanism producing spontaneous activity in a range of cells with pacemaker function. Emerging new evidence also suggests that IP(3)/ IP(3)Rs play a functional role in normal and diseased hearts and in cardiac rhythm control. Several membrane currents, including a store-operated Ca(2+) current, might be activated by Ca(2+) release from IP(3)Rs. IP(3) /IP(3)R may thus add another dimension to the complex regulation of heart rate.
%Z FOR Codes: 60602 111601 110106


%0 Journal Article
%~ PubMed
%A Zhang, Bao-Ting
%A Whitehead, Nicholas P
%A Gervasio, Othon L
%A Reardon, Trent F
%A Vale, Molly
%A Fatkin, Daine
%A Dietrich, Alexander
%A Yeung, Ella W
%A Allen, David G
%T Pathways of Ca2+ entry and cytoskeletal damage following eccentric contractions in mouse skeletal muscle.
%B Journal of Applied Physiology
%D 2012
%C United States
%I American Physiological Society
%V 112
%N 12
%P 2077-2086
%@ 1522-1601
%X Muscles that are stretched during contraction (eccentric contractions) show deficits in force production and a variety of structural changes including loss of antibody staining of cytoskeletal proteins. Extracellular Ca(2+) entry and activation of calpains have been proposed as mechanisms involved in these changes. The present study used isolated mouse extensor digitorum longus (EDL) muscles subjected to 10 eccentric contractions and monitored force production, immunostaining of cytoskeletal proteins and resting stiffness. Possible pathways for Ca(2+) entry were tested with streptomycin (200 ??M), a blocker of stretch-activated channels, and with muscles from mice deficient in the transient receptor potential canonical 1gene (TRPC1 KO), a candidate gene for stretch-activated channels. At 30 min after the eccentric contractions, the isometric force was decreased to 75 + 3 % of initial control and this force loss was reduced by streptomycin but not in the TRPC1 KO. Desmin, titin and dystrophin all showed patchy loss of immunostaining 30 min after the eccentric contractions which was substantially reduced by streptomycin and in the TRPC1 KO muscles. Muscles showed a reduction of resting stiffness following eccentric contractions and this reduction was eliminated by streptomycin and absent in the TRPC1 KO muscles. Calpain activation was determined by the appearance of a lower molecular weight autolysis product and ??-calpain was activated at 30 min whereas the muscle-specific calpain-3 was not. To test whether the loss of stiffness was caused by titin cleavage, protein gels were used but no significant titin cleavage was detected. These results suggest that Ca(2+) entry following eccentric contractions is through a stretch-activated channel that is blocked by streptomycin and encoded or modulated by TRPC1.
%Z FOR Codes: 110602 110904


%0 Book Section
%A Allen, David
%A Ju, Yue-Kun
%A Liu, Jie
%A Imtiaz, Mohammad S.
%T SOCE as a Determinant of Cardiac Pacemaker Activity
%B Store-operated Ca2+ entry (SOCE) pathways: Emerging signaling concepts in human (patho)physiology
%D 2012
%C United States
%I Springer
%V 
%N 
%P 363-367
%@ 9783709109618
%X 
%Z FOR Codes: 110201


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Trajanovska, Sofie
%T The multiple roles of phosphate in muscle fatigue.
%B Frontiers in Physiology
%D 2012
%C Switzerland
%I Frontiers Research Foundation
%V 3
%N 
%P 463
%@ 1664-042X
%X 
%Z FOR Codes: 111603 110602 110905


%0 Journal Article
%~ PubMed
%A Gervásio, Othon L
%A Phillips, William D
%A Cole, Louise
%A Allen, David G
%T Caveolae respond to cell stretch and contribute to
stretch-induced signaling.
%B Journal of Cell Science
%D 2011
%C United Kingdom
%I The Company of Biologists Ltd.
%V 124
%N Pt 21
%P 3581-3590
%@ 1477-9137
%X Caveolae are invaginations of the plasma membrane that are formed by caveolins. Caveolar membranes are also enriched in cholesterol, glycosphingolipids and signaling enzymes such as Src kinase. Here we investigate the effect of cell stretch upon caveolar dynamics and signaling. Transfection of C2 myoblasts with caveolin-3-YFP led to the formation of caveolae-like membrane pits 50-100 nm in diameter. Glycosphingolipids became immobilized and tightly packed together within caveolin-rich regions of the plasma membrane. Fluorescence resonance energy transfer (FRET) was used to assess the degree of glycosphingolipid packing. Myoblasts were subjected to a brief (1 minute) stretch on an elastic substratum. Stretch caused a reduction in glycosphingolipid FRET, consistent with a reversible unfolding of caveolar pits in response to membrane tension. Cells expressing caveolin-3-YFP also displayed an enhanced stretch-induced activation of Src kinase, as assessed by immunofluorescence. Repeated stretches resulted in the trafficking and remodeling of caveolin-3-rich membrane domains and accelerated turnover of membrane glycosphingolipids. The stretch-induced unfolding of caveolae, activation of Src and redistribution of caveolin and glycosphingolipids might reflect mechanisms of the cellular adaptation to mechanical stresses.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Ju, Yue-Kun
%A Liu, Jie
%A Lee, Bon Hyang
%A Lai, Donna
%A Woodcock, Elizabeth A
%A Lei, Ming
%A Cannell, Mark B
%A Allen, David G
%T Distribution and Functional Role of Inositol 1,4,5-trisphosphate Receptors in Mouse Sinoatrial Node.
%B Circulation research
%D 2011
%C United States
%I Lippincott Williams & Wilkins
%V 109
%N 8
%P 848-57
%@ 0009-7330
%X Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) have been implicated in the generation of arrhythmias and cardiac muscle nuclear signaling. However, in the mammalian sinoatrial node (SAN), where the heart beat originates, the expression and functional activity of IP(3)Rs have not been investigated.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Whitehead, Nicholas P
%T Duchenne muscular dystrophy-what causes the increased membrane permeability in skeletal muscle?
%B The international journal of biochemistry & cell biology
%D 2011
%C United Kingdom
%I Pergamon
%V 43
%N 3
%P 290-4
%@ 1357-2725
%X Duchenne muscular dystrophy is a severe muscle wasting disease caused by a mutation in the gene for dystrophin--a cytoskeletal protein connecting the contractile machinery to a group of proteins in the cell membrane. At the end stage of the disease there is profound muscle weakness and atrophy. However, the early stage of the disease is characterised by increased membrane permeability which allows soluble enzymes such as creatine kinase to leak out of the cell and ions such as calcium to enter the cell. The most widely accepted theory to explain the increased membrane permeability is that the absence of dystrophin makes the membrane more fragile so that the stress of contraction causes membrane tears which provide the increase in membrane permeability. However other possibilities are that increases in intracellular calcium caused by altered regulation of channels activate enzymes, such as phospholipase A(2), which cause increased membrane permeability. Increases in reactive oxygen species (ROS) are also present in the early stages of the disease and may contribute both to membrane damage by peroxidation and to the channel opening. Understanding the earliest phases of the pathology are critical to therapies directed at minimizing the muscle damage.
%Z FOR Codes: 110904 60602


%0 Journal Article
%~ PubMed
%A Westerblad, Hĺkan
%A Allen, David G
%T Emerging roles of ROS/RNS in muscle function and fatigue.
%B Antioxidants & Redox Signaling
%D 2011
%C United States
%I Mary Ann Liebert, Inc. Publishers
%V 15
%N 9
%P 2487-2499
%@ 1557-7716
%X Reactive oxygen and nitrogen species (ROS/RNS) are involved in numerous aspects of cellular signaling. Classically ROS/RNS have been associated with cellular dysfunction and disease, but it is now clear that they are also of integral importance under normal conditions. In this review, we discuss ROS/RNS effects in skeletal muscle, with special focus on changes in contractile function. The review deals with the tentative roles of ROS/RNS for acute changes that can occur during strenuous exercise resulting in muscle fatigue, for the recovery from fatigue, and for the effects of training/overtraining. We also discuss two groups of inherited diseases; muscle dystrophies, where recent data suggest that ROS/RNS may be of unexpectedly large importance, and mitochondrial myopathies, where the role of ROS seems more limited than originally thought.
%Z FOR Codes: 60602


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Clugston, Ellery
%A Petersen, Yvonne
%A Roder, Ira V
%A Chapman, Bob E
%A Rudolf, Ruediger
%T Interactions between intracellular calcium and phosphate in intact mouse muscle during fatigue.
%B Journal of applied physiology (Bethesda, Md. : 1985)
%D 2011
%C United States
%I American Physiological Society
%V 111
%N 2
%P 358-66
%@ 1522-1601
%X Fatigue was studied in intact tibialis anterior muscle of anesthetized mice. The distal tendon was detached and connected to a force transducer while blood flow continued normally. The muscle was stimulated with electrodes applied directly to the muscle surface and fatigued by repeated (1 per 4 s), brief (0.4 s), maximal (100-Hz stimulation frequency) tetani. Force declined monotonically to 49 ?? 5% of the initial value with a half time of 36 ?? 5 s and recovered to 86 ?? 4% after 4 min. Intracellular phosphate concentration ([P(i)]) was measured by (31)P-NMR on perchloric acid extracts of muscles. [P(i)] increased during fatigue from 7.6 ?? 1.7 to 16.0 ?? 1.6 mmol/kg muscle wet wt and returned to control during recovery. Intracellular Ca(2+) was measured with cameleons whose plasmids had been transfected in the muscle 2 wk before the experiment. Yellow cameleon 2 was used to measure myoplasmic Ca(2+), and D1ER was used to measure sarcoplasmic reticulum (SR) Ca(2+). The myoplasmic Ca(2+) during tetani declined steadily during the period of fatigue and showed complete recovery over 4 min. The SR Ca(2+) also declined monotonically during fatigue and showed a partial recovery with rest. These results show that the initial phase of force decline is accompanied by a rise in [P(i)] and a reduction in the tetanic myoplasmic Ca(2+). We suggest that both changes contribute to the fatigue. A likely cause of the decline in tetanic myoplasmic Ca(2+) is precipitation of CaP(i) in the SR.
%Z FOR Codes: 60602 110602


%0 Journal Article
%~ PubMed
%A Guo, Wangang
%A Shi, Xiaoqin
%A Liu, Anheng
%A Yang, Guodong
%A Yu, Fang
%A Zheng, Qiangsun
%A Wang, Zikuan
%A Allen, David G
%A Lu, Zifan
%T RNA binding protein QKI inhibits the ischemia/reperfusion-induced apoptosis in neonatal cardiomyocytes.
%B Cellular Physiology and Biochemistry
%D 2011
%C Switzerland
%I S. Karger AG
%V 28
%N 4
%P 593-602
%@ 1421-9778
%X RNA-binding protein QKI is abundantly expressed in the brain and heart. The role of QKI in the nervous system has been well characterized, but its function in cardiac muscle is still poorly understood. The present study was to investigate the role of QKI in ischemia/reperfusion-induced apoptosis in cardiomyocytes.
%Z FOR Codes: 60111


%0 Journal Article
%~ PubMed
%A Mohl, Marion C
%A Iismaa, Siiri E
%A Xiao, Xiao-Hui
%A Friedrich, Oliver
%A Wagner, Soeren
%A Nikolova-Krstevski, Vesna
%A Wu, Jianxin
%A Yu, Ze-Yan
%A Feneley, Michael
%A Fatkin, Diane
%A Allen, David G
%A Graham, Robert M
%T Regulation of murine cardiac contractility by activation of ?(1A)-adrenergic receptor-operated Ca(2+) entry.
%B Cardiovascular Research
%D 2011
%C Netherlands
%I Oxford University Press
%V 91
%N 2
%P 310-319
%@ 1755-3245
%X Sympathetic regulation of cardiac contractility is mediated in part by ?(1)-adrenergic receptors (ARs), and the ?(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about ?(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediates ?(1A)-AR-coupled cardiac contractility.
%Z FOR Codes: 110201 601


%0 Book Section
%A Allen, David
%A Ward, Marie L
%T Roles of cardiac SAC beyond mechano-electric coupling: stretch-enhanced force generation and muscular dystrophy
%B Cardiac Mechano-Electric Coupling and Arrhythmias, Second Edition
%D 2011
%C United Kingdom
%I Oxford University Press
%V 
%N 
%P 435-441
%@ 9780199570164
%E Kohl, Peter
%E Sachs, Frederick
%E Franz, Michael R.
%X 
%Z FOR Codes: 110201 1116


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Gervasio, Othon L
%A Yeung, Ella W
%A Whitehead, Nicholas P
%T Calcium and the damage pathways in muscular dystrophy.
%B Canadian Journal of Physiology and Pharmacology
%D 2010
%C Canada
%I NRC Research Press
%V 88
%N 2
%P 83-91
%@ 1205-7541
%X Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. Experiments on the mdx mouse, a model of DMD, have shown that mdx muscles are particularly susceptible to stretch-induced damage. In this review, we discuss evidence showing that a series of stretched contractions of mdx muscle fibres causes a prolonged increase in resting intracellular calcium concentration ([Ca2+]i). The rise in [Ca2+]i is caused by Ca2+ entry through a class of stretch-activated channels (SACNSC) for which one candidate gene is TRPC1. We review the evidence for activation of SACNSC in muscle by reactive oxygen species (ROS) and suggest that stretch-induced ROS production is part of the pathway that triggers increased channel activity. When the TRPC1 gene was transfected into C2 myoblasts, expression occurred throughout the cell. Only when the TRPC1 gene was coexpressed with caveolin-3 did the TRPC1 protein express in the membrane. When TRPC1 was expressed in the membrane, it could be activated by ROS to produce Ca2+ entry and this entry was inhibited by PP2, an inhibitor of src kinase. These results suggest that stretched contractions activate ROS production, which activates src kinase. Activity of this kinase causes opening of SACNSC and allows Ca2+ entry. This pathway appears to be a significant cause of muscle damage in DMD.
%Z FOR Codes: 110399 60602


%0 Journal Article
%~ PubMed
%A Whitehead, Nicholas P
%A Yeung, Ella W
%A Froehner, Stanley C
%A Allen, David G
%T Skeletal Muscle NADPH Oxidase Is Increased and Triggers Stretch-Induced Damage in the mdx Mouse.
%B PloS one
%D 2010
%C United States
%I Public Library of Science
%V 5
%N 12
%P e15354
%@ 1932-6203
%X Recent studies have shown that oxidative stress contributes to the pathogenesis of muscle damage in dystrophic (mdx) mice. In this study we have investigated the role of NADPH oxidase as a source of the oxidative stress in these mice. The NADPH oxidase subunits gp91(phox), p67(phox) and rac 1 were increased 2-3 fold in tibilais anterior muscles from mdx mice compared to wild type. Importantly, this increase occurred in 19 day old mice, before the onset of muscle necrosis and inflammation, suggesting that NADPH oxidase is an important source of oxidative stress in mdx muscle. In muscles from 9 week old mdx mice, gp91(phox) and p67(phox) were increased 3-4 fold and NADPH oxidase superoxide production was 2 times greater than wild type. In single fibers from mdx muscle NADPH oxidase subunits were all located on or near the sarcolemma, except for p67(phox),which was expressed in the cytosol. Pharmacological inhibition of NADPH oxidase significantly reduced the intracellular Ca(2+) rise following stretched contractions in mdx single fibers, and also attenuated the loss of muscle force. These results suggest that NADPH oxidase is a major source of reactive oxygen species in dystrophic muscle and its enhanced activity has a stimulatory effect on stretch-induced Ca(2+) entry, a key mechanism for muscle damage and functional impairment.
%Z FOR Codes: 110904 111699


%0 Book Section
%A Allen, David
%A Zhang, Bao-ting
%A Whitehead, Nicholas
%T Stretch-induced membrane damage in muscle: comparison of wild-type and mdx mice.
%B Advances in Experimental Medicine and Biology: Muscle Biophysics: From Molecules to Cells
%D 2010
%C United States
%I Springer New York LLC
%V 
%N 
%P 297-313
%@ 9781441963659
%E Rassier, Dilson E.
%X 
%Z FOR Codes: 1116 1109


%0 Journal Article
%~ PubMed
%A Allen, David
%A Westerblad, Hĺkan
%T What limits exercise during high-intensity aerobic exercise?
%B European journal of applied physiology
%D 2010
%C Germany
%I Springer
%V 110
%N 
%P 661-2; author reply 663-4
%@ 1439-6327
%X 
%Z FOR Codes: 1106


%0 Book Section
%A Westerblad, Hakan
%A Allen, David
%T Cellular mechanisms of skeletal muscle fatigue
%B Human Muscle Fatigue
%D 2009
%C United Kingdom
%I Routledge
%V 
%N 
%P 48-75
%@ 9780415453271
%E Williams, Craig A
%E Ratel, Sebastien
%X 
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Reardon, Trent F
%A Allen, David G
%T Iron injections in mice increase skeletal muscle iron content, induce oxidative stress and reduce exercise performance.
%B Experimental Physiology
%D 2009
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 94
%N 6
%P 720-730
%@ 1469-445X
%X Iron accelerates the production of reactive oxygen species (ROS). Excessive levels of ROS are thought to accelerate skeletal muscle fatigue and contribute to the loss of skeletal muscle mass and function with age. Patients with an iron overload disease frequently report symptoms of weakness and fatigue, which is attributed to reduced cardiac function. The contribution of skeletal muscle to these symptoms is unknown. Using a mouse model of iron overload, we determined the extent of iron accumulation in skeletal muscle and the concentrations of the iron storage protein ferritin. The level of oxidative stress, changes in antioxidant enzymes and exercise performance were also assessed. Compared with control mice, the iron overloaded mice had elevated levels of iron in the tibialis anterior muscle and a fourfold increase in ferritin light chain. The oxidative stress product malondialdehyde was increased in the iron group compared with the control group, as was the antioxidant enzyme activity of glutathione reductase and glutathione peroxidase. The iron group performed less work on an endurance test and produced less force in a strength test. Body weight and skeletal muscle weight were lower in the iron group following the intervention. Iron loading reduced the weight of the fast-twitch extensor digitorum longus muscle more than the slow-twitch soleus muscle. In summary, iron accumulation in skeletal muscle may play a significant role in the reduced exercise capacity seen in iron overload disorders and in ageing, and may play an underlying role in skeletal muscle atrophy.
%Z FOR Codes: 60602


%0 Journal Article
%~ PubMed
%A Reardon, Trent F
%A Allen, David G
%T Time to fatigue is increased in mouse muscle at 37A{degrees}C; the role of iron and ROS.
%B The Journal of physiology
%D 2009
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 587
%N 19
%P 4705-16
%@ 0022-3751
%X Studies exploring the rate of fatigue in isolated muscle at 37 degrees C have produced mixed results. In the present study, muscle fibre bundles from the mouse foot were used to study the effect of temperature on the rate of muscle fatigue. Provided iron was excluded from the solutions, time to fatigue at 37 degrees C was increased compared to 22 degrees C (125 +/- 8% of 22 degrees C fatigue time). In contrast, when iron was present (approximately 1 microM), fatigue was accelerated (68 +/- 10%). Iron can increase reactive oxygen species (ROS), which are believed to accelerate fatigue. The addition of 25-100 microM H(2)O(2) at 22 degrees C reduced time to fatigue to 80-20% of the control, respectively. Iron was added to cultured primary skeletal muscle cells to determine if iron could increase ROS production. Neither iron entry nor ROS production were detected in non-contracting muscle cells. The addition of 8-hydroxyquinoline, which facilitates iron entry, to iron-ascorbic acid solutions caused a rapid rise in intracellular iron and ROS. Our results indicate that time to fatigue in vitro is increased at 37 degrees C relative to 22 degrees C, but the addition of ROS can accelerate fatigue. An increase in muscle iron can accelerate ROS production, which may be important during or following exercise and in haemochromatosis, disuse atrophy and sarcopenia.
%Z FOR Codes: 60602


%0 Journal Article
%~ PubMed
%A Murphy, Elizabeth
%A Allen, David G
%T Why did the NHE inhibitor clinical trials fail?
%B Journal of Molecular and Cellular Cardiology
%D 2009
%C United Kingdom
%I Academic Press
%V 46
%N 2
%P 137-141
%@ 1095-8584
%X 
%Z FOR Codes: 1102 1116


%0 Book Section
%A Allen, David
%A Lamb, Graham D
%A Westerblad, Hakan
%T Cellular mechanisms of skeletal muscle fatigue
%B Physiological Bases of Human Performance during Work and Exercise
%D 2008
%C United States
%I Churchill Livingstone
%V 
%N 
%P 115-125
%@ 978-0-443-10271-4
%E Taylor, Nigel
%E Groeller, Herbert
%X 
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Allen, David G
%T Fatigue in working muscles.
%B Journal of applied physiology (Bethesda, Md. : 1985)
%D 2008
%C United States
%I American Physiological Society
%V 106
%N 0
%P 358-9
%@ 1522-1601
%X 
%Z FOR Codes: 1106


%0 Journal Article
%~ PubMed
%A Whitehead, Nicholas P
%A Pham, Catherine
%A Gervasio, Othon L
%A Allen, David G
%T N-Acetylcysteine ameliorates skeletal muscle pathophysiology in mdx mice.
%B The Journal of Physiology
%D 2008
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 586
%N 7
%P 2003-2014
%@ 0022-3751
%X Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by a mutation in the gene encoding dystrophin, a protein linking the cytoskeleton to the extracellular matrix. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) provided protection against dystrophic muscle damage in the mdx mouse, an animal model of DMD. In isolated mdx muscles, NAC prevented the increased membrane permeability and reduced the force deficit associated with stretch-induced muscle damage. Three-week-old mdx mice were treated with NAC in the drinking water for 6 weeks. Dihydroethidium staining showed that NAC treatment reduced the concentration of reactive oxygen species (ROS) in mdx muscles. This was accompanied by a significant decrease in centrally nucleated fibres in muscles from NAC-treated mdx mice. Immunoblotting showed that NAC treatment decreased the nuclear protein expression of NF-kappaB, a transcription factor involved in pro-inflammatory cytokine expression. Finally, we show that NAC treatment reduced caveolin-3 protein levels and increased the sarcolemmal expression of beta-dystroglycan and the dystrophin homologue, utrophin. Taken together, our findings suggest that ROS play an important role in the dystrophic pathogenesis, both in terms of activating damage pathways and in regulating the expression of some dystrophin-associated membrane proteins. These results offer the prospect that antioxidants such as NAC could have therapeutic potential for DMD patients.
%Z FOR Codes: 110905


%0 Journal Article
%~ PubMed
%A Zhang, Bao-Ting
%A Yeung, Simon S
%A Allen, David G
%A Qin, Ling
%A Yeung, Ella W
%T Role of the calcium-calpain pathway in cytoskeletal damage after eccentric contractions.
%B Journal of applied physiology
%D 2008
%C United States
%I American Physiological Society
%V 105
%N 1
%P 352-357
%@ 8750-7587
%X The mechanism(s) underlying eccentric damage to skeletal muscle cytoskeleton remain unclear. We examined the role of Ca(2+) influx and subsequent calpain activation in eccentric damage to cytoskeletal proteins. Eccentric muscle damage was induced by stretching isolated mouse muscles by 20% of the optimal length in a series of 10 tetani. Muscle force and immunostaining of the cytoskeletal proteins desmin, dystrophin, and titin were measured at 5, 15, 30, and 60 min after eccentric contractions and compared with the control group that was subjected to 10 isometric contractions. A Ca(2+)-free solution and leupeptin (100 microM), a calpain inhibitor, were applied to explore the role of Ca(2+) and calpain, respectively, in eccentric muscle damage. After eccentric contractions, decreases in desmin and dystrophin immunostaining were apparent after 5 min that accelerated over the next 60 min. Increased titin immunostaining, thought to indicate damage to titin, was evident 10 min after stretch, and fibronectin entry, indicating membrane disruption, was evident 20 min after stretch. These markers of damage also increased in a time-dependent manner. Muscle force was reduced immediately after stretch and continued to fall, reaching 56 +/- 2% after 60 min. Reducing extracellular calcium to zero or applying leupeptin minimized the changes in immunostaining of cytoskeletal proteins, reduced membrane disruption, and improved the tetanic force. These results suggest that the cytoskeletal damage and membrane disruption were mediated primarily by increased Ca(2+) influx into muscle cells and subsequent activation of calpain.
%Z FOR Codes: 110602


%0 Journal Article
%~ PubMed
%A Allen, D G
%A Lamb, G D
%A Westerblad, H
%T Skeletal muscle fatigue: cellular mechanisms.
%B Physiological Reviews
%D 2008
%C United States
%I American Physiological Society
%V 88
%N 1
%P 287-332
%@ 0031-9333
%X Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Many muscle properties change during fatigue including the action potential, extracellular and intracellular ions, and many intracellular metabolites. A range of mechanisms have been identified that contribute to the decline of performance. The traditional explanation, accumulation of intracellular lactate and hydrogen ions causing impaired function of the contractile proteins, is probably of limited importance in mammals. Alternative explanations that will be considered are the effects of ionic changes on the action potential, failure of SR Ca2+ release by various mechanisms, and the effects of reactive oxygen species. Many different activities lead to fatigue, and an important challenge is to identify the various mechanisms that contribute under different circumstances. Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Ward, Marie-Louise
%A Williams, Iwan A
%A Chu, Yi
%A Cooper, Patricia J
%A Ju, Yue-Kun
%A Allen, David G
%T Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy.
%B Progress in biophysics and molecular biology
%D 2008
%C United Kingdom
%I Pergamon
%V 97
%N 2-3
%P 232-249
%@ 0079-6107
%X The stretch-induced increase in force production of ventricular muscle is biphasic. An abrupt increase in force coincides with the stretch, which is then followed by a slower response that develops over minutes (the slow force response or SFR). The SFR is accompanied by a slow increase in the magnitude of the intracellular Ca2+ transient, but the stretch-dependent mechanisms that give rise to this remain controversial. We characterized the SFR using right ventricular trabeculae from mouse hearts. Application of three different blockers of stretch-activated non-selective cation channels (SAC NSC) reduced the magnitude of the SFR 60s after stretch (400 microM streptomycin: from 86+/-25% to 38+/-14%, P<0.01, n=9; 10 microM GdCl3: from 65+/-21%, to 12+/-7%, P<0.01, n=7; 10 microM GsMTx-4 from 122+/-40% to 15+/-8%, P<0.05, n=6). Streptomycin also decreased the increase in Ca2+ transient amplitude 60s after the stretch from 43.5+/-12.7% to 5.7+/-3.5% (P<0.05, n=4), and reduced the stretch-dependent increase in intracellular Ca2+ in quiescent muscles when stretched. The transient receptor potential, canonical channels TRPC1 and TRPC6 are mechano-sensitive, non-selective cation channels. They are expressed in mouse ventricular muscle, and could therefore be responsible for stretch-dependent influx of Na+ and/or Ca2+ during the SFR. Expression of TRPC1 was investigated in the mdx heart, a mouse model of Duchenne''s muscular dystrophy. Resting Ca2+ was raised in isolated myocytes from old mdx animals, which was blocked by application of SAC blockers. Expression of TRPC1 was increased in the older mdx animals, which have developed a dilated cardiomyopathy, and might therefore contribute to the dilated cardiomyopathy.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Gervásio, Othon L
%A Whitehead, Nicholas P
%A Yeung, Ella W
%A Phillips, William D
%A Allen, David G
%T TRPC1 binds to caveolin-3 and is regulated by Src kinase - role in Duchenne muscular dystrophy.
%B Journal of Cell Science
%D 2008
%C United Kingdom
%I Company of Biologists
%V 121
%N 13
%P 2246-2255
%@ 0021-9533
%X Transient receptor potential canonical 1 (TRPC1), a widely expressed calcium (Ca(2+))-permeable channel, is potentially involved in the pathogenesis of Duchenne muscular dystrophy (DMD). Ca(2+) influx through stretch-activated channels, possibly formed by TRPC1, induces muscle-cell damage in the mdx mouse, an animal model of DMD. In this study, we showed that TRPC1, caveolin-3 and Src-kinase protein levels are increased in mdx muscle compared with wild type. TRPC1 and caveolin-3 colocalised and co-immunoprecipitated. Direct binding of TRPC1-CFP to caveolin-3-YFP was confirmed in C2 myoblasts by fluorescence energy resonance transfer (FRET). Caveolin-3-YFP targeted TRPC1-CFP to the plasma membrane. Hydrogen peroxide, a reactive oxygen species (ROS), increased Src activity and enhanced Ca(2+) influx, but only in C2 myoblasts co-expressing TRPC1 and caveolin-3. In mdx muscle, Tiron, a ROS scavenger, and PP2, a Src inhibitor, reduced stretch-induced Ca(2+) entry and increased force recovery. Because ROS production is increased in mdx/DMD, these results suggest that a ROS-Src-TRPC1/caveolin-3 pathway contributes to the pathogenesis of mdx/DMD.
%Z FOR Codes: 110904


%0 Journal Article
%~ Isi
%A Korhonen, T
%A Bruton, JD
%A Westerblad, H
%A Tavi, P
%A Aydin, J
%A Allen, DG
%T Activation of Ca2+-dependent protein kinase II during repeated contractions in single muscle fibres from mouse is dependent on the frequency of sarcoplasmic reticulum Ca2+ release
%B ACTA PHYSIOLOGICA
%D 2007
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 191
%N 2
%P 131-137
%@ 1748-1708
%X 
%Z FOR Codes: 110905


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Lamb, Graham D
%A Westerblad, Hakan
%T Impaired calcium release during fatigue.
%B Journal of applied physiology (Bethesda, Md. : 1985)
%D 2007
%C United States
%I Amer Physiological Society
%V 104
%N 1
%P 296-305
%@ 8750-7587
%X Impaired calcium release from the sarcoplasmic reticulum (SR) has been identified as a contributor to fatigue in isolated skeletal muscle fibers. The functional importance of this phenomenon can be quantified by the use of agents, such as caffeine, which can increase SR Ca(2+) release during fatigue. A number of possible mechanisms for impaired calcium release have been proposed. These include reduction in the amplitude of the action potential, potentially caused by extracellular K(+) accumulation, which may reduce voltage sensor activation but is counteracted by a number of mechanisms in intact animals. Reduced effectiveness of SR Ca(2+) channel opening is caused by the fall in intracellular ATP and the rise in Mg(2+) concentrations that occur during fatigue. Reduced Ca(2+) available for release within the SR can occur if inorganic phosphate enters the SR and precipitates with Ca(2+). Further progress requires the development of methods that can identify impaired SR Ca(2+) release in intact, blood-perfused muscles and that can distinguish between the various mechanisms proposed.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Ju, Yue-Kun
%A Allen, David G
%T Store-Operated Ca(2+) Entry and TRPC Expression; Possible Roles in Cardiac Pacemaker Tissue.
%B Heart, lung & circulation
%D 2007
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 16
%N 5
%P 349-55
%@ 1443-9506
%X Store-operated Ca(2+) channels (SOCCs) were first identified in non-excitable cells by the observation that depletion of Ca(2+) stores caused increased influx of extracellular Ca(2+). Recent studies have suggested that SOCCs might be related to the transient receptor potential (TRPC) gene family. The mechanism of cardiac pacemaking involves voltage-dependent pacemaker current; in addition there is growing evidence that intracellular sarcoplasmic reticulum (SR) Ca(2+) release plays an important role. In the present short review we assess preliminary evidence for Ca(2+) entry related to SR store depletion and expression of TRPCs in pacemaker tissue. These newer findings suggest that Ca(2+) entry and inward current triggered by store depletion might also contribute to the pacemaker current. Many hormones, drugs and interventions such as ischaemia and stretch, which alter Ca(2+) handling, will also modulate pacemaker firing thought their effect on SOCCs.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Ju, Yue-Kun
%A Chu, Yi
%A Chaulet, Herve
%A Lai, Donna
%A Gervasio, Othon L
%A Graham, Robert M
%A Cannell, Mark B
%A Allen, David G
%T Store-operated Ca2+ influx and expression of TRPC genes in mouse sinoatrial node.
%B Circulation research
%D 2007
%C United States
%I Lippincott Williams & Wilkins
%V 100
%N 11
%P 1605-1614
%@ 1524-4571
%X Store-operated Ca(2+) entry was investigated in isolated mouse sinoatrial nodes (SAN) dissected from right atria and loaded with Ca(2+) indicators. Incubation of the SAN in Ca(2+)-free solution caused a substantial decrease in resting intracellular Ca(2+) concentration ([Ca(2+)](i)) and stopped pacemaker activity. Reintroduction of Ca(2+) in the presence of cyclopiazonic acid (CPA), a sarcoplasmic reticulum Ca(2+) pump inhibitor, led to sustained elevation of [Ca(2+)](i), a characteristic of store-operated Ca(2+) channel (SOCC) activity. Two SOCC antagonists, Gd(3+) and SKF-96365, inhibited 72+/-8% and 65+/-8% of this Ca(2+) influx, respectively. SKF-96365 also reduced the spontaneous pacemaker rate to 27+/-4% of control in the presence of CPA. Because members of the transient receptor potential canonical (TRPC) gene family may encode SOCCs, we used RT-PCR to examine mRNA expression of the 7 known mammalian TRPC isoforms. Transcripts for TRPC1, 2, 3, 4, 6, and 7, but not TRPC5, were detected. Immunohistochemistry using anti-TRPC1, 3, 4, and 6 antibodies revealed positive labeling in the SAN region and single pacemaker cells. These results indicate that mouse SAN exhibits store-operated Ca(2+) activity which may be attributable to TRPC expression, and suggest that SOCCs may be involved in regulating pacemaker firing rate.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Williams, Iwan A
%A Allen, David G
%T THE ROLE OF REACTIVE OXYGEN SPECIES IN THE HEARTS OF DYSTROPHIN-DEFICIENT (MDX) MICE.
%B American journal of physiology. Heart and circulatory physiology
%D 2007
%C United States
%I American Physiological Society
%V 293
%N 3
%P H1969-77
%@ 0363-6135
%X Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. Oxidative stress is thought to contribute to the skeletal muscle damage in DMD; however, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The dystrophin-deficient (mdx) mouse is an animal model of DMD that also lacks dystrophin. The current study investigates the role of the antioxidant N-acetylcysteine (NAC) on mdx cardiomyocyte function, Ca(2+) handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 wk. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased dihydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca(2+) handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca(2+) sensitivity; NAC treatment returned mdx fractional shortening to WT values but did not affect the Ca(2+) sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of collagen type III and the macrophage-specific protein, CD68; NAC-treatment returned collagen type III and CD68 expression close to WT values. Finally, mdx hearts had increased NADPH oxidase activity, suggesting it could be a possible source of increased reactive oxygen species in mdx mice. This study is the first to demonstrate that oxidative damage may be involved in the pathogenesis of the heart failure that occurs in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Williams, Iwan
%A Xiao, Xiao-Hui
%A Ju, Yue-Kun
%A Allen, David
%T The rise of [Na(+)] (i) during ischemia and reperfusion in the rat heart-underlying mechanisms.
%B Pflugers Arch
%D 2007
%C Germany
%I Springer
%V 454
%N 
%P 903-12
%@ 0031-6768
%X Intracellular Na(+) concentration ([Na(+)](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na(+)](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+) overload. Part of the rise of [Na(+)](i) during ischemia may be caused by increased activity of the cardiac Na(+)/H(+) exchanger (NHE1), activated by the ischemic rise in [H(+)](i). In support of this view, NHE1 inhibitors reduce the [Na(+)](i) rise during ischemia. Another possibility is that the rise of [Na(+)](i) during ischemia is caused by Na(+) influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na(+) channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 microM) and TTX (300 nM) prevented the rise in [Na(+)](i) during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na(+)](i) on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na(+) currents. At the concentrations used, TTX reduced the transient Na(+) current (I (Na)) by 11 +/- 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na(+) current (I (Na,P)) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I (Na,P) to 41 +/- 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na(+)](i) during ischemia is by blockade of I (Na,P). The fact that a low concentration of TTX eliminated the rise of [Na(+)](i) during ischemia suggests that I (Na,P) is a major source of Na(+) influx in this model of ischemia.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Allen, David G
%A Westerblad, Hakan
%T Understanding muscle from its length.
%B The Journal of physiology
%D 2007
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 583
%N 1
%P 3-4
%@ 0022-3751
%X 
%Z FOR Codes: 110905


%0 Journal Article
%~ PubMed
%A Moopanar, Terence
%A Xiao, Xiao-Hui
%A Jiang, Lele
%A Chen, Zhi-Ping
%A Kemp, Bruce
%A Allen, David
%T AICAR inhibits the Na+/H+ exchanger in rat hearts--possible contribution to cardioprotection.
%B Pflugers Arch
%D 2006
%C Germany
%I Springer-Verlag
%V 453
%N 2
%P 147-56
%@ 0031-6768
%X AICAR (5-amino-1-beta-D: -ribofuranosyl-imidazole-4-carboxamide) is an adenosine analog which improves the recovery of the heart after ischemia. In some tissues AICAR enters cells and stimulates AMP-activated protein kinase (AMPK). We explored the mechanism of cardioprotection in isolated rat hearts. We confirmed that AICAR (0.5 mM) applied 10 min prior to a 30-min period of ischemia and present throughout ischemia and reperfusion caused a substantial improvement in the recovery of developed pressure on reperfusion. However, adenosine (100 microM) produced no improvement, suggesting that the mechanism of action of AICAR was not increased endogenous adenosine production. Measurements of intracellular sodium concentration ([Na(+)](i)) showed that AICAR prevented the rapid rise of [Na(+)](i), which normally occurs on reperfusion. Inhibitors of the cardiac sodium-hydrogen exchanger (NHE1) also protect the heart from ischemic damage and also prevent the rapid rise of [Na(+)](i) on reperfusion, suggesting that AICAR might cause the inhibition of NHE1. We tested this possibility on isolated rat ventricular myocytes in which the recovery of pH(i) after NH(4)Cl exposure provides a measure of NHE1 activity. AICAR (0.5 micromM) inhibited NHE1 activity in response to an acid load by about 80%. To test whether the AICAR-induced inhibition of NHE1 arose through adenosine, we used the adenosine receptor blocker 8-sulfophenyltheophylline (8-SPT) and found that it had no measureable effect. To test whether the AICAR-induced inhibition of NHE1 might occur through the activation of AMPK, we measured the activity of two isoforms of AMPK. Surprisingly, activity was reduced, whereas in many other tissues AICAR increases AMPK activity. Furthermore, this effect of AMPK was blocked by 8-SPT, suggesting that the inhibition of AMPK arose through an adenosine-receptor-related pathway. We conclude that AICAR inhibits NHE1 through an unidentified pathway. This inhibition may make a contribution to the cardioprotective effects of AICAR.
%Z FOR Codes: 111699


%0 Journal Article
%~ PubMed
%A Kizana, E
%A Ginn, S L
%A Smyth, C M
%A Boyd, A
%A Thomas, S P
%A Allen, D G
%A Ross, D L
%A Alexander, I E
%T Fibroblasts modulate cardiomyocyte excitability: implications for cardiac gene therapy.
%B Gene therapy
%D 2006
%C United Kingdom
%I Nature Publishing Group
%V 13
%N 
%P 1611-5
%@ 0969-7128
%X In an earlier study exploring the potential of gene transfer to repair myocardial conduction defects, we observed that myotubes, generated by forced expression of MyoD, exhibit reduced excitability when also modified to express connexin43 (Cx43). We hypothesized that this effect was caused by gap junction-mediated coupling between myotubes and the underlying fibroblast feeder layer. This intriguing possibility has important implications for ongoing efforts to develop strategies for repairing myocardial conduction defects by gene transfer, and also provides novel insights into the electrophysiological function of naturally occurring heterologous cell coupling within the heart. Although a conductive function for fibroblasts through heterologous coupling has previously been reported, the current study provides novel evidence that fibroblasts can modulate cardiomyocyte excitability in a Cx43-dependent manner. In a co-culture study system, neonatal rat cardiomyocytes were grown on monolayers of mouse fibroblasts with genetically altered Cx43 expression and the effect on intrinsic beat frequency examined. Cardiomyocytes grown on wild-type (WT) fibroblasts expressing native levels of Cx43 beat significantly slower than cells grown on fibroblasts devoid of this molecule (germline knockout) or with dominant-negative functional suppression. Expression of Cx43 in fibroblasts from Cx43 knockout mice restored cardiomyocyte beat frequency, to rates comparable with those observed in co-culture with WT fibroblasts.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Williams, Iwan A
%A Allen, David G
%T Intracellular calcium handling in ventricular myocytes from mdx mice.
%B American journal of physiology. Heart and circulatory physiology
%D 2006
%C United States
%I American Physiological Society
%V 292
%N 
%P H846-55
%@ 0363-6135
%X Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.
%Z FOR Codes: 111699


%0 Journal Article
%~ PubMed
%A Tsoutsman, Tatiana
%A Chung, Jessica
%A Doolan, Alessandra
%A Nguyen, Lan
%A Williams, Iwan A
%A Tu, Emily
%A Lam, Lien
%A Bailey, Charles G
%A Rasko, John E J
%A Allen, David G
%A Semsarian, Christopher
%T Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
%B Journal of molecular and cellular cardiology
%D 2006
%C UK
%I Academic Press
%V 41
%N 4
%P 623-32
%@ 0022-2828
%X Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC). Little is known about how cTnI mutations cause disease. Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner. Mice were compared to transgenic mice that overexpress normal cTnI (cTnI-wt) and non-transgenic littermates (NTG). cTnI-G203S mice developed all the characteristic features of FHC by age 21 weeks. Left ventricular hypertrophy was observed on echocardiography (1.25+/-0.05 mm vs. 0.86+/-0.02 mm in cTnI-wt, P<0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP. Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice. Expression of the cTnI-G203S mutation in neonatal cardiomyocytes resulted in a significant increase in myocyte volume, and reduced interactions with both troponins T and C. Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S mice, with a prolonged decay constant in Ca2+ transients and a reduced decay constant in response to caffeine treatment. Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC. The cTnI-G203S mutation disrupts interactions with partner proteins, and results in intracellular Ca2+ dysregulation early in life, suggesting a pathogenic role in development of FHC.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Whitehead, Nicholas P
%A Yeung, Ella W
%A Allen, David G
%T Muscle damage in mdx (dystrophic) mice: role of calcium and reactive oxygen species.
%B Clinical and experimental pharmacology & physiology
%D 2006
%C Australia
%I Blackwell Publishing Asia
%V 33
%N 7
%P 657-62
%@ 0305-1870
%X 1. Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease caused by a genetic mutation that leads to the complete absence of the cytoskeletal protein dystrophin in muscle fibres. 2. The present review provides an overview of some of the physiological pathways that may contribute to muscle damage and degeneration in DMD, based primarily on experimental findings in the mdx mouse, an animal model of this disease. 3. A rise in intracellular calcium is widely thought to be an important initiating event in the dystrophic pathogenesis. The pathway(s) leading to increased intracellular calcium in dystrophin deficient muscle is uncertain, but recent work from our laboratory provides evidence that stretch-activated channels are an important source of the calcium influx. Other possible routes of calcium entry are also discussed. 4. The consequences of elevated cytosolic calcium may include activation of proteases, such as calpain, and increased production of reactive oxygen species (ROS), which can cause protein and membrane damage. 5. Another possible cause of damage in dystrophic muscle involves inflammatory pathways, such as those mediated by neutrophils, macrophages and associated cytokines. There is recent evidence that increased ROS may be important in both the activation of and the damage caused by this inflammatory pathway in mdx muscle.
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Whitehead, Nicholas P
%A Streamer, Margaret
%A Lusambili, Lynn I
%A Sachs, Frederick
%A Allen, David G
%T Streptomycin reduces stretch-induced membrane permeability in muscles from mdx mice.
%B Neuromuscular disorders : NMD
%D 2006
%C United Kingdom
%I Elsevier Ltd.
%V 16
%N 12
%P 845-54
%@ 0960-8966
%X It is well-known that muscles from mdx mice are more susceptible to membrane damage from eccentric contractions than wild-type muscles. The present study tested the hypothesis that the stretch-induced membrane permeability in dystrophic muscle is due to Ca(2+) entry through stretch-activated channels (SACs) and the subsequent activation of Ca(2+) -dependent degradative pathways. Eccentric contractions were carried out on muscles from mdx and wild-type mice, both on isolated muscles and on intact mice subjected to downhill running on a treadmill. In isolated muscles the SAC blockers, streptomycin and GsMTx4, improved force and significantly reduced the uptake of procion orange dye into fibres from mdx muscles, which increased progressively over 60 min after the eccentric contractions. In experiments on intact mdx mice, streptomycin also partially prevented the reduced force and the increased membrane permeability (Evans Blue Dye uptake). The results suggest that Ca(2+) entry through SACs activates Ca(2+) -dependent pathways, which are the main cause of the increased membrane permeability in mdx muscle.
%Z FOR Codes: 111699


%0 Journal Article
%~ PubMed
%A Moopanar, Terence R
%A Allen, David G
%T The activity-induced reduction of myofibrillar Ca2+ sensitivity in mouse skeletal muscle is reversed by dithiothreitol.
%B The Journal of physiology
%D 2006
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 571
%N Pt 1
%P 191-200
%@ 0022-3751
%X The aim of this study was to further characterize the reduction of myofibrillar Ca2+ sensitivity in mouse muscle which has been observed after fatigue at 37 degrees C. Muscle bundles and single fibres were isolated from mouse flexor digitorum brevis muscle and studied at 37 degrees C. The single fibres were injected with the Ca2+ indicator indo-1. Muscle fatigue was produced by 0.4 s tetani repeated at 4 s intervals until force had fallen to less than 50% of initial. Excitation-contraction coupling was assessed by measuring the cytosolic calcium concentration ([Ca2+]i) during tetani, and the maximum Ca2+-activated force and the myofibrillar Ca2+ sensitivity were estimated from a series of tetani at different stimulation frequencies. Two main results were found. (i) The reduction of Ca2+ sensitivity only occurred when the muscle was intensely stimulated leading to fatigue. When the muscle was rested for 10 min at 37 degrees C there was no significant change in Ca2+ sensitivity. (ii) If the membrane-permeant thiol-specific reducing agent dithiothreitol (0.5 mm) was applied to the muscle for 2 min following the fatigue protocol, the reduction in Ca2+ sensitivity was reversed. Dithiothreitol had no effect on Ca2+ sensitivity in unfatigued preparations. There was no effect of fatigue or dithiothreitol on tetanic [Ca2+]i or on the maximum Ca2+-activated force. These results suggest that intense activity of skeletal muscle at 37 degrees C causes the production of reactive oxygen species which oxidize a target protein. We propose that critical sulphydryl groups on the target protein(s) are converted to disulphide bonds and this reaction reduces Ca2+ sensitivity.
%Z FOR Codes: 111601


%0 Journal Article
%~ Isi
%A Chu, Y.
%A Allen, D.
%A Ju, Y. K.
%T The immunolocalization of TRPC1 in mouse sino-atrial node.
%B Journal of Molecular and Cellular Cardiology
%D 2006
%C UK
%I Academic Press
%V 41
%N 4
%P 735-735
%@ 0022-2828
%X 
%Z FOR Codes: 111601


%0 Journal Article
%~ PubMed
%A Allen, David G
%T Why stretched muscles hurt--is there a role for half-sarcomere dynamics?
%B The Journal of physiology
%D 2006
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 573
%N Pt 1
%P 4
%@ 0022-3751
%X 
%Z FOR Codes: 111601