Lactic acid restores skeletal muscle force in an in vitro fatigue model: are voltage-gated chloride channels involved?

High interstitial K+ concentration ([K+]) has been reported to impede normal propagation of electrical impulses along the muscle cell membrane (sarcolemma) and then also into the transverse tubule system; this is one considered underlying mechanism associated with the development of muscle fatigue. Interestingly, the extracellular buildup of lactic acid, once considered an additional cause for muscle fatigue, was recently shown to have force-restoring effects in such conditions. Specifically, it was proposed that elevated lactic acid (and intracellular acidosis) may lead to inhibition of voltage-gated chloride channels, thereby reestablishing better excitability of the muscle cell sarcolemma. In the present study, using an in vitro muscle contractile experimental setup to study functionally viable rectus abdominis muscle preparations obtained from normal swine, we examined the effects of 20 mM lactic acid and 512 μM 9-anthracenecarboxylic acid (9-AC; a voltage-gated chloride channel blocker) on the force recovery of K+-depressed (10 mM K+) twitch forces. We observed a similar muscle contractile restoration after both treatments. Interestingly, at elevated [K+], myotonia (i.e., hyperexcitability or afterdepolarizations), usually present in skeletal muscle with inherent or induced chloride channel dysfunctions, was not observed in the presence of either lactic acid or 9-AC. In part, these data confirm previous studies showing a force-restoring effect of lactic acid in high-[K+] conditions. In addition, we observed similar restorative effects of lactic acid and 9-AC, implicating a beneficial mechanism via voltage-gated chloride channel modulation.

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Ataluren increases functional expression of R894X mutant skeletal muscle voltage gated chloride channels in vitro

Neuromuscular Disorders ◽

10.1016/s0960-8966(18)30376-6 ◽

2018 ◽

Vol 28 ◽

pp. S29

Author(s):

K. Suetterlin ◽

E. Matthews ◽

R. Männikkö ◽

M.G. Hanna

Keyword(s):

Skeletal Muscle ◽

Chloride Channels ◽

Functional Expression ◽

Voltage Gated

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Muscle Fatigue: Lactic Acid or Inorganic Phosphate the Major Cause?

Physiology ◽

10.1152/physiologyonline.2002.17.1.17 ◽

2002 ◽

Vol 17 (1) ◽

pp. 17-21 ◽

Cited By ~ 59

Author(s):

Håkan Westerblad ◽

David G. Allen ◽

Jan Lännergren

Keyword(s):

Skeletal Muscle ◽

Lactic Acid ◽

Muscle Fatigue ◽

Muscle Function ◽

Inorganic Phosphate ◽

Creatine Phosphate ◽

Intracellular Acidosis ◽

Skeletal Muscle Fatigue ◽

Mammalian Muscle ◽

Acid Accumulation

Intracellular acidosis due mainly to lactic acid accumulation has been regarded as the most important cause of skeletal muscle fatigue. Recent studies on mammalian muscle, however, show little direct effect of acidosis on muscle function at physiological temperatures. Instead, inorganic phosphate, which increases during fatigue due to breakdown of creatine phosphate, appears to be a major cause of muscle fatigue.

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pH of isolated resting skeletal muscle and its relation to potassium content

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1963.204.6.1048 ◽

1963 ◽

Vol 204 (6) ◽

pp. 1048-1054 ◽

Cited By ~ 30

Author(s):

Ronald B. Miller ◽

Ian Tyson ◽

Arnold S. Relman

Keyword(s):

Skeletal Muscle ◽

Intracellular Ph ◽

Potassium Content ◽

Ion Concentration ◽

Detectable Effect ◽

Rat Diaphragm ◽

Intracellular Acidosis ◽

Experimental Conditions ◽

Hydrogen Ion Concentration

Intracellular pH of isolated rat diaphragm was measured with both a C14-DMO method and a tissue CO2 technique. The values for intracellular pH by each method, although slightly different, changed in parallel under most experimental conditions. Acute, severe potassium depletion in vitro had no detectable effect on intracellular pH, nor did prior depletion in vivo followed by incubation in a potassium-free bath. This was true whether or not the potassium-depleted muscle was exposed to normal or elevated extracellular levels of bicarbonate, and was unaffected by the presence of cationic amino acids in the bath. Acute repletion of previously potassium-depleted muscle resulted in a small rise in cell pH, but this was no greater than that produced by loading normal tissues with potassium. It is concluded that under the conditions of these experiments there is no evidence of intracellular acidosis in potassium-depleted skeletal muscle. Rat diaphragm can lose up to half its potassium content in vitro without detectable increase in hydrogen ion concentration.

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In vitro evaluation of antidiabetic potential of hesperidin and its aglycone hesperetin under oxidative stress in skeletal muscle cell line

Cell Biochemistry and Function ◽

10.1002/cbf.3478 ◽

2020 ◽

Vol 38 (4) ◽

pp. 419-427 ◽

Cited By ~ 3

Author(s):

R. Dhanya ◽

P. Jayamurthy

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Cell Line ◽

Muscle Cell ◽

Skeletal Muscle Cell ◽

In Vitro Evaluation ◽

Skeletal Muscle Cell Line ◽

Muscle Cell Line

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Activation of Utrophin Promoter by Heregulin via theets-related Transcription Factor Complex GA-binding Protein α/β

Molecular Biology of the Cell ◽

10.1091/mbc.10.6.2075 ◽

1999 ◽

Vol 10 (6) ◽

pp. 2075-2086 ◽

Cited By ~ 84

Author(s):

Tejvir S. Khurana ◽

Alan G. Rosmarin ◽

Jing Shang ◽

Thomas O. B. Krag ◽

Saumya Das ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Transcription Factors ◽

Neuromuscular Junction ◽

Muscle Cell ◽

Cell Cultures ◽

Binding Protein ◽

Duchenne's Muscular Dystrophy ◽

Ga Binding Protein

Utrophin/dystrophin-related protein is the autosomal homologue of the chromosome X-encoded dystrophin protein. In adult skeletal muscle, utrophin is highly enriched at the neuromuscular junction. However, the molecular mechanisms underlying regulation of utrophin gene expression are yet to be defined. Here we demonstrate that the growth factor heregulin increases de novo utrophin transcription in muscle cell cultures. Using mutant reporter constructs of the utrophin promoter, we define the N-box region of the promoter as critical for heregulin-mediated activation. Using this region of the utrophin promoter for DNA affinity purification, immunoblots, in vitro kinase assays, electrophoretic mobility shift assays, and in vitro expression in cultured muscle cells, we demonstrate thatets-related GA-binding protein α/β transcription factors are activators of the utrophin promoter. Taken together, these results suggest that the GA-binding protein α/β complex of transcription factors binds and activates the utrophin promoter in response to heregulin-activated extracellular signal–regulated kinase in muscle cell cultures. These findings suggest methods for achieving utrophin up-regulation in Duchenne’s muscular dystrophy as well as mechanisms by which neurite-derived growth factors such as heregulin may influence the regulation of utrophin gene expression and subsequent enrichment at the neuromuscular junction of skeletal muscle.

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Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00264.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. G942-G947 ◽

Cited By ~ 150

Author(s):

Michael Camilleri ◽

Adil E. Bharucha ◽

Ryuji Ueno ◽

Duane Burton ◽

George M. Thomforde ◽

...

Keyword(s):

Healthy Volunteers ◽

Chloride Channel ◽

Chloride Channels ◽

Gastrointestinal Transit ◽

Intestinal Secretion ◽

Gastric Volume ◽

Colonic Transit ◽

Controlled Study ◽

Double Blind

Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 μg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink (“satiation”) test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

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Arachidonic acid supplementation enhances in vitro skeletal muscle cell growth via a COX-2-dependent pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00038.2012 ◽

2013 ◽

Vol 304 (1) ◽

pp. C56-C67 ◽

Cited By ~ 42

Author(s):

James F. Markworth ◽

David Cameron-Smith

Keyword(s):

Skeletal Muscle ◽

Arachidonic Acid ◽

Cell Growth ◽

Muscle Cell ◽

Myogenic Differentiation ◽

Skeletal Muscle Cell ◽

Diverse Range ◽

Cox 2 ◽

Dependent Pathway

Arachidonic acid (AA) is the metabolic precursor to a diverse range of downstream bioactive lipid mediators. A positive or negative influence of individual eicosanoid species [e.g., prostaglandins (PGs), leukotrienes, and hydroxyeicosatetraenoic acids] has been implicated in skeletal muscle cell growth and development. The collective role of AA-derived metabolites in physiological states of skeletal muscle growth/atrophy remains unclear. The present study aimed to determine the direct effect of free AA supplementation and subsequent eicosanoid biosynthesis on skeletal myocyte growth in vitro . C2C12 (mouse) skeletal myocytes induced to differentiate with supplemental AA exhibited dose-dependent increases in the size, myonuclear content, and protein accretion of developing myotubes, independent of changes in cell density or the rate/extent of myogenic differentiation. Nonselective (indomethacin) or cyclooxygenase 2 (COX-2)-selective (NS-398) nonsteroidal anti-inflammatory drugs blunted basal myogenesis, an effect that was amplified in the presence of supplemental free AA substrate. The stimulatory effects of AA persisted in preexisting myotubes via a COX-2-dependent (NS-389-sensitive) pathway, specifically implying dependency on downstream PG biosynthesis. AA-stimulated growth was associated with markedly increased secretion of PGF2α and PGE2; however, incubation of myocytes with PG-rich conditioned medium failed to mimic the effects of direct AA supplementation. In vitro AA supplementation stimulates PG release and skeletal muscle cell hypertrophy via a COX-2-dependent pathway.

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Dietary fish oil delays hypoxic skeletal muscle fatigue and enhances caffeine-stimulated contractile recovery in the rat in vivo hindlimb

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0501 ◽

2017 ◽

Vol 42 (6) ◽

pp. 613-620 ◽

Cited By ~ 3

Author(s):

Gregory E. Peoples ◽

Peter L. McLennan

Keyword(s):

Skeletal Muscle ◽

Fish Oil ◽

Muscle Fatigue ◽

Contractile Function ◽

Physiological Role ◽

Muscle Bundle ◽

Skeletal Muscle Fatigue ◽

Dietary Fish ◽

Contractile Recovery ◽

Muscle Contractile

Oxygen efficiency influences skeletal muscle contractile function during physiological hypoxia. Dietary fish oil, providing docosahexaenoic acid (DHA), reduces the oxygen cost of muscle contraction. This study used an autologous perfused rat hindlimb model to examine the effects of a fish oil diet on skeletal muscle fatigue during an acute hypoxic challenge. Male Wistar rats were fed a diet rich in saturated fat (SF), long-chain (LC) n-6 polyunsaturated fatty acids (n-6 PUFA), or LC n-3 PUFA DHA from fish oil (FO) (8 weeks). During anaesthetised and ventilated conditions (normoxia 21% O2 (SaO2–98%) and hypoxia 14% O2 (SaO2–89%)) the hindlimb was perfused at a constant flow and the gastrocnemius–plantaris–soleus muscle bundle was stimulated via sciatic nerve (2 Hz, 6–12V, 0.05 ms) to established fatigue. Caffeine (2.5, 5, 10 mM) was supplied to the contracting muscle bundle via the arterial cannula to assess force recovery. Hypoxia, independent of diet, attenuated maximal twitch tension (normoxia: 82 ± 8; hypoxia: 41 ± 2 g·g−1 tissue w.w.). However, rats fed FO sustained higher peak twitch tension compared with the SF and n-6 PUFA groups (P < 0.05), and the time to decline to 50% of maximum twitch tension was extended (SF: 546 ± 58; n-6 PUFA: 522 ± 58; FO: 792 ± 96 s; P < 0.05). In addition, caffeine-stimulated skeletal muscle contractile recovery was enhanced in the FO-fed animals (SF: 41 ± 3; n-6 PUFA: 40 ± 4; FO: 52 ± 7% recovery; P < 0.05). These results support a physiological role of DHA in skeletal muscle membranes when exposed to low-oxygen stress that is consistent with the attenuation of muscle fatigue under physiologically normoxic conditions.

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The Influence of Supplemental Dietary Linoleic Acid on Skeletal Muscle Contractile Function in a Rodent Model of Barth Syndrome

Frontiers in Physiology ◽

10.3389/fphys.2021.731961 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mario Elkes ◽

Martin Andonovski ◽

Daislyn Vidal ◽

Madison Farago ◽

Ryan Modafferi ◽

...

Keyword(s):

Skeletal Muscle ◽

Linoleic Acid ◽

Muscle Function ◽

Barth Syndrome ◽

Dietary Linoleic Acid ◽

Skeletal Muscle Function ◽

Contractile Phenotype ◽

Muscle Contractile

Barth syndrome is a rare and incurable X-linked (male-specific) genetic disease that affects the protein tafazzin (Taz). Taz is an important enzyme responsible for synthesizing biologically relevant cardiolipin (for heart and skeletal muscle, cardiolipin rich in linoleic acid), a critical phospholipid of mitochondrial form and function. Mutations to Taz cause dysfunctional mitochondria, resulting in exercise intolerance due to skeletal muscle weakness. To date, there has been limited research on improving skeletal muscle function, with interventions focused on endurance and resistance exercise. Previous cell culture research has shown therapeutic potential for the addition of exogenous linoleic acid in improving Taz-deficient mitochondrial function but has not been examined in vivo. The purpose of this study was to examine the influence of supplemental dietary linoleic acid on skeletal muscle function in a rodent model of Barth syndrome, the inducible Taz knockdown (TazKD) mouse. One of the main findings was that TazKD soleus demonstrated an impaired contractile phenotype (slower force development and rates of relaxation) in vitro compared to their WT littermates. Interestingly, this impaired contractile phenotype seen in vitro did not translate to altered muscle function in vivo at the whole-body level. Also, supplemental linoleic acid attenuated, to some degree, in vitro impaired contractile phenotype in TazKD soleus, and these findings appear to be partially mediated by improvements in cardiolipin content and resulting mitochondrial supercomplex formation. Future research will further examine alternative mechanisms of dietary supplemental LA on improving skeletal muscle contractile dysfunction in TazKD mice.

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