Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle

SUMMARYDuring normal animal movements, the forces produced by the locomotor muscles may be greater than, equal to or less than the forces acting on those muscles, the consequences of which significantly affect both the maximum force produced and the energy consumed by the muscles. Lengthening (eccentric)contractions result in the greatest muscle forces at the lowest relative energetic costs. Eccentric contractions play a key role in storing elastic strain energy which, when recovered in subsequent contractions, has been shown to result in enhanced force, work or power outputs. We present data that support the concept that this ability of muscle to store and recover elastic strain energy is an adaptable property of skeletal muscle. Further, we speculate that a crucial element in that muscle spring may be the protein titin. It too seems to adapt to muscle use, and its stiffness seems to be`tuned' to the frequency of normal muscle use.

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Oxidative stress restores force loss in skeletal muscle following eccentric contractions

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.801.24 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Andrés Hernández ◽

Natalia Kosterina ◽

Abe Katz ◽

Håkan Westerblad

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Eccentric Contractions

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Eccentric exercise markedly increases c-Jun NH2-terminal kinase activity in human skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.5.1668 ◽

1999 ◽

Vol 87 (5) ◽

pp. 1668-1673 ◽

Cited By ~ 62

Author(s):

Marni D. Boppart ◽

Doron Aronson ◽

Lindsay Gibson ◽

Ronenn Roubenoff ◽

Leslie W. Abad ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Eccentric Exercise ◽

Intracellular Signaling ◽

Human Skeletal Muscle ◽

Vastus Lateralis ◽

Fold Increase ◽

Mitogen Activated Protein Kinase ◽

Eccentric Contractions ◽

Vastus Lateralis Muscle

Eccentric contractions require the lengthening of skeletal muscle during force production and result in acute and prolonged muscle injury. Because a variety of stressors, including physical exercise and injury, can result in the activation of the c-Jun NH2-terminal kinase (JNK) intracellular signaling cascade in skeletal muscle, we investigated the effects of eccentric exercise on the activation of this stress-activated protein kinase in human skeletal muscle. Twelve healthy subjects (7 men, 5 women) completed maximal concentric or eccentric knee extensions on a KinCom isokinetic dynamometer (10 sets, 10 repetitions). Percutaneous needle biopsies were obtained from the vastus lateralis muscle 24 h before exercise (basal), immediately postexercise, and 6 h postexercise. Whereas both forms of exercise increased JNK activity immediately postexercise, eccentric contractions resulted in a much higher activation (15.4 ± 4.5 vs. 3.5 ± 1.4-fold increase above basal, eccentric vs. concentric). By 6 h after exercise, JNK activity decreased back to baseline values. In contrast to the greater activation of JNK with eccentric exercise, the mitogen-activated protein kinase kinase 4, the immediate upstream regulator of JNK, was similarly activated by concentric and eccentric exercise. Because the activation of JNK promotes the phosphorylation of a variety of transcription factors, including c-Jun, the results from this study suggest that JNK may be involved in the molecular and cellular adaptations that occur in response to injury-producing exercise in human skeletal muscle.

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Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00192.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. C411-C419 ◽

Cited By ~ 52

Author(s):

Elisabeth R. Barton

Keyword(s):

Skeletal Muscle ◽

Mechanical Load ◽

Eccentric Contraction ◽

Eccentric Contractions ◽

Normal Muscle ◽

Glycoprotein Complex ◽

Dystrophin Glycoprotein Complex ◽

Severe Pathology ◽

Murine Skeletal Muscle ◽

Dystrophin Glycoprotein

Loss of the dystrophin glycoprotein complex (DGC) or a subset of its components can lead to muscular dystrophy. However, the patterns of symptoms differ depending on which proteins are affected. Absence of dystrophin leads to loss of the entire DGC and is associated with susceptibility to contractile injury. In contrast, muscles lacking γ-sarcoglycan (γ-SG) display little mechanical fragility and still develop severe pathology. Animals lacking dystrophin or γ-SG were used to identify DGC components critical for sensing dynamic mechanical load. Extensor digitorum longus muscles from 7-wk-old normal (C57), dystrophin- null ( mdx), and γ-SG-null ( gsg−/−) mice were subjected to a series of eccentric contractions, after which ERK1/2 phosphorylation levels were determined. At rest, both dystrophic strains had significantly higher ERK1 phosphorylation, and gsg−/− muscle also had heightened ERK2 phosphorylation compared with wild-type controls. Eccentric contractions produced a significant and transient increase in ERK1/2 phosphorylation in normal muscle, whereas the mdx strain displayed no significant proportional change of ERK1/2 phosphorylation after eccentric contraction. Muscles from gsg−/− mice had no significant increase in ERK1 phosphorylation; however, ERK2 phosphorylation was more robust than in C57 controls. The reduction in mechanically induced ERK1 phosphorylation in gsg−/− muscle was not dependent on age or severity of phenotype, because muscle from both young and old (age 20 wk) animals exhibited a reduced response. Immunoprecipitation experiments revealed that γ-SG was phosphorylated in normal muscle after eccentric contractions, indicating that members of the DGC are modified in response to mechanical perturbation. This study provides evidence that the SGs are involved in the transduction of mechanical information in skeletal muscle, potentially unique from the entire DGC.

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Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

AJP Cell Physiology ◽

10.1152/ajpcell.00456.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. C476-C488 ◽

Cited By ~ 53

Author(s):

Paul T. Martin ◽

Rui Xu ◽

Louise R. Rodino-Klapac ◽

Elaine Oglesbay ◽

Marybeth Camboni ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Transgenic Mice ◽

Skeletal Muscles ◽

Eccentric Contractions ◽

Cytotoxic T Cell ◽

Muscle Pathology ◽

Mdx Mice ◽

Specific Force ◽

Wild Type

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

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Connective tissue regeneration in skeletal muscle after eccentric contraction-induced injury

Journal of Applied Physiology ◽

10.1152/japplphysiol.00577.2016 ◽

2017 ◽

Vol 122 (3) ◽

pp. 533-540 ◽

Cited By ~ 16

Author(s):

Abigail L. Mackey ◽

Michael Kjaer

Keyword(s):

Skeletal Muscle ◽

Connective Tissue ◽

Human Skeletal Muscle ◽

Matrix Protein ◽

Eccentric Contraction ◽

Eccentric Contractions ◽

Optimal Timing ◽

Type I ◽

Strong Response ◽

Experimental Conditions

Human skeletal muscle has the potential to regenerate completely after injury induced under controlled experimental conditions. The events inside the myofibers as they undergo necrosis, followed closely by satellite cell-mediated myogenesis, have been mapped in detail. Much less is known about the adaptation throughout this process of both the connective tissue structures surrounding the myofibers and the fibroblasts, the cells responsible for synthesizing this connective tissue. However, the few studies investigating muscle connective tissue remodeling demonstrate a strong response that appears to be sustained for a long time after the major myofiber responses have subsided. While the use of electrical stimulation to induce eccentric contractions vs. voluntary eccentric contractions appears to lead to a greater extent of myofiber necrosis and regenerative response, this difference is not apparent when the muscle connective tissue responses are compared, although further work is required to confirm this. Pharmacological agents (growth hormone and angiotensin II type I receptor blockers) are considered in the context of accelerating the muscle connective tissue adaptation to loading. Cautioning against this, however, is the association between muscle matrix protein remodeling and protection against reinjury, which suggests that a (so far undefined) period of vulnerability to reinjury may exist during the remodeling phases. The role of individual muscle matrix components and their spatial interaction during adaptation to eccentric contractions is an unexplored field in human skeletal muscle and may provide insight into the optimal timing of rest vs. return to activity after muscle injury.

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EFFECTS OF ECCENTRIC CONTRACTIONS ON IN VITRO Na+-K+-ATPase ACTIVITY AND SARCOPLASMIC RETICULUM Ca2+-SEQUESTERING IN RAT SKELETAL MUSCLE

Japanese Journal of Physical Fitness and Sports Medicine ◽

10.7600/jspfsm.59.337 ◽

2010 ◽

Vol 59 (4) ◽

pp. 337-348 ◽

Cited By ~ 4

Author(s):

KEITA KANZAKI ◽

MAI KURATANI ◽

SATOSHI MATSUNAGA ◽

TAKAAKI MISHIMA ◽

SACHIO USUI ◽

...

Keyword(s):

Skeletal Muscle ◽

Sarcoplasmic Reticulum ◽

Atpase Activity ◽

Eccentric Contractions ◽

Rat Skeletal Muscle

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Effect of prior eccentric contractions on lactate/H+ transport in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.3.e554 ◽

1998 ◽

Vol 274 (3) ◽

pp. E554-E559 ◽

Cited By ~ 5

Author(s):

Henriette Pilegaard ◽

Sven Asp

Keyword(s):

Skeletal Muscle ◽

Buffer Capacity ◽

Ph Regulation ◽

Eccentric Contractions ◽

Lactate Transport ◽

Giant Vesicles ◽

Muscle Lactate ◽

Muscle Ph ◽

Supramaximal Stimulation ◽

Muscle Types

The effect of prior eccentric contractions on skeletal muscle lactate/H+transport was investigated in rats. Lactate transport was measured in sarcolemmal giant vesicles obtained from soleus and red (RG) and white gastrocnemii (WG) muscles 2 days after intense eccentric contractions (ECC) and from the corresponding contralateral control (CON) muscles. The physiochemical buffer capacity was determined in the three muscle types from both ECC and CON legs. Furthermore, the effect of prior eccentric contractions on release and muscle content of lactate and H+ during and after supramaximal stimulation was examined using the perfused rat hindlimb preparation. The lactate transport rate was lower ( P < 0.05) in vesicles obtained from ECC-WG (29%) and ECC-RG (13%) than in vesicles from the CON muscles. The physiochemical buffer capacity was reduced ( P < 0.05) in ECC-WG (13%) and ECC-RG (9%) compared with the corresponding CON muscles. There were only marginal effects on the soleus muscle. Muscle lactate concentrations and release of lactate during recovery from intense isometric contractions were lower ( P< 0.05) in ECC than in CON hindlimbs, indicating decreased anaerobic glycogenolysis. In conclusion, the sarcolemmal lactate/H+ transport capacity and the physiochemical buffer capacity were reduced in prior eccentrically stimulated WG and RG in rats, suggesting that muscle pH regulation may be impaired after unaccustomed eccentric exercise. In addition, the data indicate that the glycogenolytic potential is decreased in muscles exposed to prior eccentric contractions.

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