Browsing by Subject "Muscle contraction"

Now showing 1 - 5 of 5
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    Increased Resurgent Sodium Currents (INaR) in Inherited and Acquired Disorders of Excitability
    (2012-08-07) Piekarz, Andrew D.; Cummins, Theodore R.; Nicol, Grant D.; Vasko, Michael R.; Hudmon, Andrew; Khanna, Rajesh
    Voltage-gated sodium channels (VGSCs) are dynamic membrane spanning proteins which mediate the rapid influx of Na+ during the upstroke of the action potential (AP). In addition to the large inward Na+ currents responsible for the upstroke of the AP, some VGSC isoforms produce smaller, subthreshold Na+ currents, which can influence the excitable properties of neurons. An example of such a subthreshold current is resurgent Na+ current (INaR). These unusual currents are active during repolarization of the membrane potential, where the channel is normally refractory to activity. INaR exhibit slow gating kinetics and unusual voltage-dependence derived from a novel mechanism of channel inactivation which allows the channel to recover through an open configuration resulting in membrane depolarization early in the falling phase of the AP, ultra-fast re-priming of channels, and multiple AP spikes. Although originally identified in fast spiking central nervous system (CNS) neurons, INaR has recently been observed in a subpopulation of peripheral dorsal root ganglion (DRG) neurons. Because INaR is believed to contribute to spontaneous and high frequency firing of APs, I have hypothesized that increased INaR may contribute to ectopic AP firing associated with inherited and acquired disorders of excitability. Specifically, this dissertation explores the mechanisms which underlie the electrogenesis of INaR in DRG neurons and determines whether the biophysical properties of these unique currents were altered by mutations that cause inherited muscle and neuronal channelopathies or in an experimental model of nerve injury. The results demonstrate that (1) multiple Na+ channel isoforms are capable of producing INaR in DRG neurons, including NaV1.3, NaV1.6, and NaV1.7, (2) inherited muscle and neuronal channelopathIy mutations that slow the rate of channel inactivation increase INaR amplitude, (3) temperature sensitive INaR produced by select skeletal muscle channelopthy mutations may contribute to the triggering of cold-induced myotonia, and (4) INaR amplitude and distribution is significantly increased two weeks post contusive spinal cord injury (SCI). Taken together, results from this dissertation provide foundational knowledge of the properties and mechanism of INaR in DRG neurons and indicates that increased INaR likely contributes to the enhanced membrane excitability associated with multiple inherited and acquired disorders of excitability.
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    Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle
    (Springer Nature, 2018-11-30) Olthoff, John T.; Lindsay, Angus; Abo-Zahrah, Reem; Baltgalvis, Kristen A.; Patrinostro, Xiaobai; Belanto, Joseph J.; Yu, Dae-Yeul; Perrin, Benjamin J.; Garry, Daniel J.; Rodney, George G.; Lowe, Dawn A.; Ervasti, James M.; Biology, School of Science
    Force loss in skeletal muscle exposed to eccentric contraction is often attributed to injury. We show that EDL muscles from dystrophin-deficient mdx mice recover 65% of lost force within 120 min of eccentric contraction and exhibit minimal force loss when the interval between contractions is increased from 3 to 30 min. A proteomic screen of mdx muscle identified an 80% reduction in the antioxidant peroxiredoxin-2, likely due to proteolytic degradation following hyperoxidation by NADPH Oxidase 2. Eccentric contraction-induced force loss in mdx muscle was exacerbated by peroxiredoxin-2 ablation, and improved by peroxiredoxin-2 overexpression or myoglobin knockout. Finally, overexpression of γcyto- or βcyto-actin protects mdx muscle from eccentric contraction-induced force loss by blocking NADPH Oxidase 2 through a mechanism dependent on cysteine 272 unique to cytoplasmic actins. Our data suggest that eccentric contraction-induced force loss may function as an adaptive circuit breaker that protects mdx muscle from injurious contractions.
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    Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries.
    (PLOS, 2016) Chen, Xingjuan; Li, Wennan; Hiett, S. Christopher; Obukhov, Alexander G.; Department of Cellular & Integrative Physiology, IU School of Medicine
    Voltage-gated Kv7 channels are inhibited by agonists of Gq-protein-coupled receptors, such as histamine. Recent works have provided evidence that inhibition of vascular Kv7 channels may trigger vessel contractions. In this study, we investigated how Kv7 activity modulates the histamine-induced contractions in “healthy” and metabolic syndrome (MetS) pig right coronary arteries (CAs). We performed isometric tension and immunohistochemical studies with domestic, lean Ossabaw, and MetS Ossabaw pig CAs. We found that neither the Kv7.2/Kv7.4/Kv7.5 activator ML213 nor the general Kv7 inhibitor XE991 altered the tension of CA rings under preload, indicating that vascular Kv7 channels are likely inactive in the preloaded rings. Conversely, ML213 potently dilated histamine-pre-contracted CAs, suggesting that Kv7 channels are activated during histamine applications and yet partially inhibited by histamine. Immunohistochemistry analysis revealed strong Kv7.4 immunostaining in the medial and intimal layers of the CA wall, whereas Kv7.5 immunostaining intensity was strong in the intimal but weak in the medial layers. The medial Kv7 immunostaining was significantly weaker in MetS Ossabaw CAs as compared to lean Ossabaw or domestic CAs. Consistently, histamine-pre-contracted MetS Ossabaw CAs exhibited attenuated ML213-dependent dilations. In domestic pig CAs, where medial Kv7 immunostaining intensity was stronger, histamine-induced contractions spontaneously decayed to ~31% of the peak amplitude within 4 minutes. Oppositely, in Ossabaw CAs, where Kv7 immunostaining intensity was weaker, the histamine-induced contractions were more sustained. XE991 pretreatment significantly slowed the decay rate of histamine-induced contractions in domestic CAs, supporting the hypothesis that increased Kv7 activity correlates with a faster rate of histamine-induced contraction decay. Alternatively, XE991 significantly decreased the amplitude of bradykinin-dependent dilations in pre-contracted CAs. We propose that in CAs, a decreased expression or a loss of function of Kv7 channels may lead to sustained histamine-induced contractions and reduced endothelium-dependent relaxation, both risk factors for coronary spasm.
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    Pilot randomized trial of the effect of antibacterial mouthwash on muscle contractile function in healthy young adults
    (Public Library of Science, 2025-02-12) Gallardo, Edgar J.; Zoughaib, William S.; Singhal, Ahaan; Hoffman, Richard L.; Coggan, Andrew R.; Exercise & Kinesiology, School of Health and Human Sciences
    Antiseptic mouthwash use is widespread due to its oral health benefits. However, its impact on systemic physiological processes, particularly nitric oxide (NO) bioavailability and muscle contractility, is not fully understood. We sought to determine the effects of cetylpyridinium (antibacterial) versus sodium chloride (control) mouthwashes on salivary and breath NO markers and muscle contractile function in healthy young adults. Thirty participants (n = 15/group) completed a randomized, parallel-arm, blinded trial, comparing the two mouthwashes before and after 7 d of treatment. NO bioavailability was inferred via measurement of salivary nitrate (NO3-), nitrite (NO2-), and cyclic guanyl monophosphate (cGMP) concentrations and breath NO level. Contractile function of the knee extensor muscles was determined via isokinetic dynamometry. No changes in salivary NO3-, NO2-, or cGMP or in breath NO were observed in response to either treatment. However, cetylpyridinium mouthwash reduced the percentage of NO2- in saliva (17 ± 10% vs. 25 ± 13%; p = 0.0036). Peak torque at velocities of 0-6.28 rad/s was unaffected by mouthwash use. Calculated maximal knee extensor velocity (Vmax) and power (Pmax) were therefore also unchanged. Cetylpyridinium mouthwash reduces the relative abundance of NO2- in the oral cavity but does not significantly diminish overall NO bioavailability or impair muscle contractile function in healthy young adults.