Joseph D. Bruton

Karolinska Institutet

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Håkan Westerblad

Karolinska Institutet

Jan Lännergren

Karolinska Institutet

Arthur J. Cheng

York University

Johanna T. Lanner

Karolinska Institutet

Shi‐Jin Zhang

North Sichuan Medical University

Abram Katz

Swedish School of Sport and Health Sciences

Niklas Ivarsson

Karolinska Institutet

Takashi Yamada

Shizuoka City Hospital

Pasi Tavi

University of Eastern Finland

Nicolas Place

University of Lausanne

Cooperative Institutions

Karolinska Institutet

130

Queen's University Belfast

Karolinska University Hospital

University College Dublin

Trinity College Dublin

Weatherford College

Konkoly Observatory

Royal Astronomical Society

Astronomical Observatory

University of Ulster

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

What does the membrane K_ATP channel really do in skeletal muscle?

The Journal of Physiology (2010)

Joseph D. Bruton

In this issue of The Journal of Physiology, Boudreault et al. (2010) present an interesting phenomenon resulting from inactivation or absence of the skeletal muscle surface membrane KATP channel. Muscles with non-functional KATP channels were subjected to two fatigue protocols separated by at least 15 min. During the second fatigue protocol compared to the first, tetanic force was maintained at a higher level, and the concentration of free myoplasmic Ca2+ ([Ca2+]i) and force during the inter-tetanic intervals showed only modest increases. The reason for the improved performance in the second fatigue protocol remains unclear. The KATP channel is abundant in the sarcolemma of striated muscle. It consists of four Kir6.x subunits that form the pore and four SURx ATP binding subunits (for recent review see Flagg et al. 2010). As the name suggests, ATP is the controller of the channel keeping it closed when [ATP] is above 1 mm (Spruce et al. 1985). Other modulators of the KATP channel, e.g. H+, PIP2, and phosphorylation, have also been described but at normal [ATP]i, their effect is modest. Interestingly, electrophysiological, pharmacological and gene analysis data indicate that while the predominant form of the striated muscle KATP channel is composed of Kir6.2 and SUR2A complexes, there can also be significant levels of Kir6.1, SUR2B and SUR1 in some muscles. The Kir6.1 and Kir6.2 pores have widely different conductances (35 and 80 pS, repectively) and this together with the heterogeneity of the SUR subunits underlies the maximal KATP current density seen in different mouse muscles, ranging from 10 pA μm−2 in the slow soleus to 80 pA μm−2 in the fast tibialis anterior (Tricario et al. 2006). The striking behaviour of the channel in opening at low levels of ATP led to its examination as a factor in muscle fatigue. A decline in muscle force or power output (commonly called fatigue) occurs when muscles are repeatedly contracted. Exercise involves a huge increase in ATP consumption and an attractive hypothesis advanced was that as [ATP]i declines, muscle KATP channels would open, partially depolarise the membrane and impair action potential activated release of Ca2+ from the sarcoplasmic reticulum. Thus, there would be a beneficial effect in that muscle energy consumption would be reduced. Despite the fact that [ATP]i rarely falls by more than 25% even during intensive exercise, the concept of ATP compartmentalisation and possibility of far greater declines in [ATP] close to the surface membrane KATP channel allowed this hypothesis to thrive. Pharmacological manipulations of the membrane KATP channel have yielded equivocal results. Opening the channel accelerated the loss of force but so too, in many but not all experiments, did blockers of the membrane KATP channel. When Kir6.2 knockout mice were tested, it was obvious that tetanic force production was markedly less than in wild-type mice. Fatigue developed more rapidly in muscles from Kir6.2 knockout mice than in those from wild-type mice (Cifelli et al. 2007). Boudreault et al. show in the present study that this rapid development of fatigue could be largely prevented by an earlier fatigue run. Thus, the role of KATP channels in fatigue is dubious. If the membrane KATP channel is not important in fatigue, then what is its role? One clue comes from the finding in the present paper of Boudreault et al. that muscles with non-functional membrane KATP channels have a slower recovery of force after the end of the fatiguing exercise. This slower recovery of force after exercise was preceded by a marked elevation in inter-tetanic concentration of internal Ca2+, which entered the muscle cells through verapamil sensitive channels, presumably L-type channels. It is well known that prolonged elevated [Ca2+]i leads to impaired force production and locally activates Ca2+-dependent proteases (Murphy & Lamb, 2009). Thus, the presence of functional membrane KATP channels may assist in limiting the influx of Ca2+ during sustained contractile activity. But for the fortunate individual without a mutation of Kir6.2 or the SUR subunits of the KATP channel, this is not a factor that will limit exercise capacity. Mutations of the subunits in the membrane KATP channel that lead to clinical manifestations are fortunately rare. One of the better known is the developmental delay, epilepsy and neonatal diabetes (DEND) syndrome which is accompanied by muscle flaccidity and motor impairment. Recently, a mouse model carrying a human mutation known to produce the DEND syndrome was developed. When expressed only in the muscles, no muscle or motor deficit was observed. However, when expressed in neurons, clear muscle and motor impairments were found (Clark et al. 2010). These results again reiterate the point that under normal daily activities, non-functional KATP channels in the membrane of skeletal muscle have little consequence but when the isolated muscle is fatigued to the extreme in vitro, some impairment may be seen.

Sarcolemma

Kir6.2

10.1113/jphysiol.2010.200097

Cite

Citations (4)

The Twitch Interpolation Technique May Overestimate Central Fatigue

Medicine & Science in Sports & Exercise (2008)

Nicolas Place Takashi Yamada Joseph D. Bruton Håkan Westerblad

The non-invasive twitch interpolation technique is classically used in humans in order to determine the level of central fatigue: if an extra force is induced by the electrical stimulation during a contraction, then neural drive to the muscle is considered to be submaximal. However the relationship between force and myoplasmic free [Ca2+] ([Ca2+]i) during fatigue could affect the extra force production associated with the stimulation. PURPOSE: To determine the effects of an extra pulse on [Ca2+]i and the associated force during repeated tetani in single muscle fibres. METHODS: Intact, single muscle fibres were dissected from flexor digitorum brevis muscles of NMRI mice. Fibres were mounted in a chamber equipped with a force transducer and [Ca2+]i was measured with the fluorescent Ca2+ indicator indo-1. The experimental protocol involved 70-Hz tetani (350 ms) repeated at 3-s intervals until 40% initial force with an extra pulse applied every 5 tetani. The increase in [Ca2+]i and force (Δ, expressed in %) due to the extra pulse were calculated relative to their respective levels without superimposition. RESULTS: Delta force regularly increased during fatigue from 9.0 ± 1.4 at the start to 18.9 ± 1.1% tetanic force at the end of the fatigue run (p<0.05). Despite non-significant (p=0.07), Δ[Ca2+]i increased (+35.8 ± 5.8% at the start vs. +63.2 ± 18.9% tetanic [Ca2+]i at 80% of initial force) and then diminished to values lower than those measured at the start of the fatigue bout (+15.5 ± 1.6% of tetanic [Ca2+]i at 40% initial force). These results fit the non-linear force-[Ca2+]i relationship, where changes in the [Ca2+]i or the Ca2+ sensitivity have a greater impact on force at the end compared to the beginning of the fatigue run. CONCLUSION: Fatigue-induced impairment in central drive assessed with the twitch interpolation technique should be interpreted cautiously as the extra force response also depends on the force-[Ca2+]i relationship during prolonged activity. Supported by the Swedish Institute (210/0024/2006).

Muscle Fatigue

Force transducer

Tetanic stimulation

10.1249/01.mss.0000322287.70674.8f

Cite

Citations (0)

IMPAIRED MYOFIBRILLAR FUNCTION IN SOLEUS MUSCLE OF MICE WITH COLLAGEN-INDUCED ARTHRITIS

The Journal of Physiological Sciences (2009)

Takashi Yamada Joseph D. Bruton Nicolas Place Shi‐Jin Zhang Natalia Kosterina

Myofibril

Source

Cite

Citations (0)

Impaired myofibrillar function in the soleus muscle of mice with collagen‐induced arthritis

Arthritis & Rheumatism (2009)

Takashi Yamada Nicolas Place Natalia Kosterina Therese Östberg Shi‐Jin Zhang

Abstract Objective Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) in the soleus, a major postural muscle, in mice with collagen‐induced arthritis (CIA). Methods Muscle contractility and [Ca 2+ ] i were assessed in whole muscle and intact single‐fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3‐nitrotyrosine (3‐NT), carbonyl, malondialdehyde (MDA), and S‐nitrosocysteine (SNO‐Cys). Results The tetanic force per cross‐sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca 2+ ] i transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3‐NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO‐Cys content in myosin heavy‐chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA. Conclusion These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite‐induced modifications in myofibrillar proteins.

Contractility

Myofibril

Nitrotyrosine

Tropomyosin

10.1002/art.24907

Cite

Citations (49)

Frog skeletal muscle fibers recovering from fatigue have reduced charge movement.

Journal of Muscle Research and Cell Motility (2000)

Joseph D. Bruton Péter Szentesi Jan Lännergren Håkan Westerblad László Kovács

10.1023/a:1005609405435

Cite

Citations (13)

Effects of HMGB1 on in vitro responses of isolated muscle fibers and functional aspects in skeletal muscles of idiopathic inflammatory myopathies

The FASEB Journal (2009)

Cecilia Grundtman Joseph D. Bruton Takashi Yamada Therese Östberg David S. Pisetsky

Idiopathic inflammatory myopathies (IIMs) are heterogeneous rheumatic disorders of unknown cause characterized by muscle weakness, inflammatory cell infiltrates, and major histocompatibility complex (MHC) class I expression on muscle fibers. The nonhistone nuclear protein alarmin high-mobility group box 1 protein (HMGB1) has been detected extranuclearly in muscle biopsies from patients with IIMs. We hypothesize that HMGB1 has a central role in the cause of muscle weakness, particularly in the early phases of IIMs. Experiments were performed on skeletal muscle fibers isolated from adult mice, which were exposed to recombinant interferon (IFN)-γ or HMGB1. The myoplasmic free [Ca2+] was measured. Stimulation with IFN-γ resulted in increased HMGB1 expression in muscle nuclei and the myoplasm. Exposure to HMGB1 induced a reversible up-regulation of MHC class I in the muscle fibers. However, HMGB1 exposure caused an irreversible decrease in Ca2+ release from the sarcoplasmic reticulum during fatigue, induced by repeated tetanic contractions. HMGB1 and MHC class I were frequently colocalized in the myoplasm of muscle fibers in muscle biopsies from patients with early IIMs. However, HMGB1-expressing fibers outnumbered fibers expressing MHC class I. Our data indicate that HMGB1 could be an early inducer of skeletal muscle dysfunction in IIMs.—Grundtman, C., Bruton, J., Yamada, T., Östberg, T., Pisetsky, D. S., Harris, H. E., Andersson, U., Lundberg, I. E., Westerblad, H. Effects of HMGB1 on in vitro responses of isolated muscle fibers and functional aspects in skeletal muscles of idiopathic inflammatory myopathies. FASEB J. 24, 570–578 (2010). www.fasebj.org

HMGB1

Muscle weakness

10.1096/fj.09-144782

Cite

Citations (75)

Doublet Discharges Improve Force During Fatigue in Single Fibers

The FASEB Journal (2012)

Arthur J. Cheng Joseph D. Bruton Håkan Westerblad

Doublet discharge is the brief high discharge of motor units recorded at the very onset of a voluntary muscle contraction, which increases both force and maximal rate of force development in submaximal contractions. However, whether doublet discharges ameliorate or worsen fatigue‐induced reductions in force have not been investigated. Methods Twenty‐four mechanically‐dissected intact single fibers from flexor digitorum brevis muscles of C57 mice were injected with indo‐1 to assess free myoplasmic tetanic Ca 2+ ([Ca 2+ ] i ). Fatigue was induced with 150 brief 60 ms tetani every 300 ms, using either a constant frequency 70 Hz stimulation protocol or a doublet stimulation protocol that added a 200 Hz interpulse interval at the start of 70 Hz constant frequency trains. Results During the first 25 contractions of the fatigue protocol, doublets produced greater force‐time integral and peak force compared with the constant frequency tetani. There was no significant difference between protocols in the plateau tetanic force loss from contractions 50 up to 150. No significant differences in mean tetanic [Ca 2+ ] i were observed between the two stimulation fatigue protocols. Conclusion Without requiring greater mean tetanic [Ca 2+ ] i than constant frequency stimulation, our findings show that initial doublets increase tetanic force in early but not late stages of fatigue. Supported by The Swedish Research Council

Tetanic stimulation

Muscle Fatigue

Time constant

10.1096/fasebj.26.1_supplement.1078.40

Cite

Citations (0)

Biosynthesis of streptomycin. V. Origin of the formyl carbon atom of streptose

Biochimica et Biophysica Acta (BBA) - General Subjects (1969)

Joseph D. Bruton William H. Horner

Carbon atom

Carbon fibers

10.1016/0304-4165(69)90279-7

Cite

Citations (5)

Reactive oxygen species and glucose transport during exercise

Physiology News (2007)

Marie Sandström Shi‐Jin Zhang Joseph D. Bruton José Cláudio da Silva Michael B. Reid

Oxygen transport

10.36866/pn.66.16

Cite

Citations (0)

Ca2+ and force during dynamic contractions in mouse intact skeletal muscle fibers

Scientific Reports (2024)

Atsuki Fukutani Håkan Westerblad Kent Jardemark Joseph D. Bruton

Abstract Muscle fiber force production is determined by the excitation frequency of motor nerves, which induce transient increases in cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) and the force-generating capacity of the actomyosin cross-bridges. Previous studies suggest that, in addition to altered cross-bridge properties, force changes during dynamic (concentric or eccentric) contraction might be affected by Ca 2+ -dependent components. Here we investigated this by measuring [Ca 2+ ] i and force in mouse muscle fibers undergoing isometric, concentric, and eccentric contractions. Intact single muscle fibers were dissected from the flexor digitorum brevis muscle of mice. Fibers were electrically activated isometrically at 30–100 Hz and after reaching the isometric force plateau, they were actively shortened or stretched. We calculated the ratio (relative changes) in force and [Ca 2+ ] i attained in submaximal (30 Hz) and near-maximal (100 Hz) contractions under isometric or dynamic conditions. Tetanic [Ca 2+ ] i was similar during isometric, concentric and eccentric phases of contraction at given stimulation frequencies while the forces were clearly different depending on the contraction types. The 30/100 Hz force ratio was significantly lower in the concentric (44.1 ± 20.3%) than in the isometric (50.3 ± 20.4%) condition ( p = 0.005), whereas this ratio did not differ between eccentric and isometric conditions ( p = 0.186). We conclude that the larger force decrease by decreasing the stimulation frequency during concentric than during isometric contraction is caused by decreased myofibrillar Ca 2+ sensitivity, not by the decreased [Ca 2+ ] i .

Myofibril

10.1038/s41598-023-51100-5

Cite

Citations (2)