We investigate the mechanisms behind muscle adaptations and maladaptations in disease. We are also investigating the fundamental causes of muscle fatigue.
The original focus of our research group is cellular mechanisms of skeletal muscle fatigue. We also study mechanisms behind muscle adaptations in response to training and maladaptations in disease, e.g. mitochondrial myopathies.
To a large extent our research relates to the complex interactions between force production, intracellular calcium handling, mitochondrial function and reactive oxygen/nitrogen species.
Our experiments are performed on adult muscle, including unique methods to study isolated fully intact muscle fibers. We find this essential because the functions we are studying differ markedly between adult muscle and immature muscle cells/muscle-like cell lines.
Cellular mechanisms of skeletal muscle fatigue
Mechanisms behind skeletal muscle fatigue and recovery are studied mainly in single muscle fibres, but also in exercising human subjects. Mechanisms studied at present include the involvement of structural and functional changes in the intracellular Ca2+ release channels (the ryanodine receptors), reactive oxygen/nitrogen species (ROS), glycogen, and temperature effects.
Mechanisms underlying the impaired muscle function associated with common diseases
Numerous common diseases are associated with muscle weakness and early fatigue development. This can be due to muscle wasting, but also to intrinsic problems in the muscle cells leading to decreased force production. We are studying mechanisms behind muscle dysfunctions in mouse models of, for example, mitochondrial myopathies. Our results show that the altered interactions between cellular Ca2+ handling, mitochondrial function and ROS metabolism are important in dysfunctional muscles.
We have an arsenal of techniques to study skeletal muscle function. These include unique methods to study single, fully intact fibers dissected from mouse, rat and human muscles.
We use standard fluorescence and confocal microscopy to measure ions and ROS in isolated muscle cells. Analytical biochemistry is used to measure muscle metabolites, enzyme activities and protein expression.
Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle.
Cheng AJ, Willis SJ, Zinner C, Chaillou T, Ivarsson N, Ørtenblad N, et al
J. Physiol. (Lond.) 2017 12;595(24):7413-7426
Prolonged force depression after mechanically demanding contractions is largely independent of Ca2+ and reactive oxygen species.
Kamandulis S, de Souza Leite F, Hernández A, Katz A, Brazaitis M, Bruton JD, et al
FASEB J. 2017 11;31(11):4809-4820
Intramuscular Contributions to Low-Frequency Force Potentiation Induced by a High-Frequency Conditioning Stimulation.
Cheng AJ, Neyroud D, Kayser B, Westerblad H, Place N
Front Physiol 2017 ;8():712
Mechanical isolation, and measurement of force and myoplasmic free [Ca2+] in fully intact single skeletal muscle fibers.
Cheng AJ, Westerblad H
Nat Protoc 2017 Sep;12(9):1763-1776
Neuromuscular electrical stimulation prevents skeletal muscle dysfunction in adjuvant-induced arthritis rat.
Himori K, Tatebayashi D, Kanzaki K, Wada M, Westerblad H, Lanner JT, et al
PLoS ONE 2017 ;12(6):e0179925
Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+ Handling.
Cheng AJ, Place N, Westerblad H
Cold Spring Harb Perspect Med 2018 02;8(2):
Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.
Himori K, Abe M, Tatebayashi D, Lee J, Westerblad H, Lanner JT, et al
PLoS ONE 2017 ;12(2):e0169146
Dietary nitrate markedly improves voluntary running in mice.
Ivarsson N, Schiffer TA, Hernández A, Lanner JT, Weitzberg E, Lundberg JO, et al
Physiol. Behav. 2017 01;168():55-61
The Ca2+ sensitizer CK-2066260 increases myofibrillar Ca2+ sensitivity and submaximal force selectively in fast skeletal muscle.
Hwee DT, Cheng AJ, Hartman JJ, Hinken AC, Lee K, Durham N, et al
J. Physiol. (Lond.) 2017 03;595(5):1657-1670
The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome.
Llano-Diez M, Sinclair J, Yamada T, Zong M, Fauconnier J, Zhang SJ, et al
PLoS ONE 2016 ;11(12):e0167090
Mechanisms of force depression caused by different types of physical exercise studied by direct electrical stimulation of human quadriceps muscle.
Skurvydas A, Mamkus G, Kamandulis S, Dudoniene V, Valanciene D, Westerblad H
Eur. J. Appl. Physiol. 2016 Dec;116(11-12):2215-2224
Impaired Ca(2+) release contributes to muscle weakness in a rat model of critical illness myopathy.
Llano-Diez M, Cheng AJ, Jonsson W, Ivarsson N, Westerblad H, Sun V, et al
Crit Care 2016 Aug;20(1):254
Muscle Fatigue Affects the Interpolated Twitch Technique When Assessed Using Electrically-Induced Contractions in Human and Rat Muscles.
Neyroud D, Cheng AJ, Bourdillon N, Kayser B, Place N, Westerblad H
Front Physiol 2016 ;7():252
Dietary nitrate improves cardiac contractility via enhanced cellular Ca²⁺ signaling.
Pironti G, Ivarsson N, Yang J, Farinotti AB, Jonsson W, Zhang SJ, et al
Basic Res. Cardiol. 2016 May;111(3):34
Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans.
Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, et al
Am. J. Physiol., Cell Physiol. 2016 May;310(10):C836-40
Reactive oxygen/nitrogen species and contractile function in skeletal muscle during fatigue and recovery.
Cheng AJ, Yamada T, Rassier DE, Andersson DC, Westerblad H, Lanner JT
J. Physiol. (Lond.) 2016 09;594(18):5149-60
Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise.
Place N, Ivarsson N, Venckunas T, Neyroud D, Brazaitis M, Cheng AJ, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Dec;112(50):15492-7
Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy.
Gineste C, Hernandez A, Ivarsson N, Cheng AJ, Naess K, Wibom R, et al
Hum. Mol. Genet. 2015 Dec;24(23):6580-7
Intracellular Ca(2+)-handling differs markedly between intact human muscle fibers and myotubes.
Olsson K, Cheng AJ, Alam S, Al-Ameri M, Rullman E, Westerblad H, et al
Skelet Muscle 2015 ;5():26
Muscle dysfunction associated with adjuvant-induced arthritis is prevented by antioxidant treatment.
Yamada T, Abe M, Lee J, Tatebayashi D, Himori K, Kanzaki K, et al
Skelet Muscle 2015 ;5():20
Antioxidant treatments do not improve force recovery after fatiguing stimulation of mouse skeletal muscle fibres.
Cheng AJ, Bruton JD, Lanner JT, Westerblad H
J. Physiol. (Lond.) 2015 Jan;593(2):457-72
α-Actinin-3: why gene loss is an evolutionary gain.
Ivarsson N, Westerblad H
PLoS Genet. 2015 Jan;11(1):e1004908