Physiology Commons^™

Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén

Physiology Faculty Publications

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP).

METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were …

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

Alzheimer's Disease Genetics And Abca7 Splicing, Jared B. Vasquez, James F. Simpson, Ryan Harpole, Steven Estus

Physiology Faculty Publications

Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer’s disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended …

Reduced Skeletal Muscle Satellite Cell Number Alters Muscle Morphology After Chronic Stretch But Allows Limited Serial Sarcomere Addition, Matthew C. Kinney, Sudarshan Dayanidhi, Peter B. Dykstra, John J. Mccarthy, Charlotte A. Peterson, Richard L. Lieber

Physiology Faculty Publications

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. Methods: A transgenic Pax7‐DTA mouse model underwent conditional SC depletion, and their soleii were then stretch‐immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Results: Mice in the SC‐reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross‐sectional …

Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell

Physiology Faculty Publications

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …

Myonuclear Transcription Is Responsive To Mechanical Load And Dna Content But Uncoupled From Cell Size During Hypertrophy, Tyler J. Kirby, Rooshil M. Patel, Timothy S. Mcclintock, Esther E. Dupont-Versteegden, Charlotte A. Peterson, John J. Mccarthy

Physiology Faculty Publications

Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number …

Mechanical Conflict System: A Novel Operant Method For The Assessment Of Nociceptive Behavior, Steven E. Harte, Jessica B. Meyers, Renee R. Donahue, Bradley K. Taylor, Thomas J. Morrow

Physiology Faculty Publications

A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

Rfx Transcription Factors Are Essential For Hearing In Mice, Ran Elkon, Beatrice Milon, Laura Morrison, Manan Shah, Sarath Vijayakumar, Manoj Racherla, Carmen C. Leitch, Lorna Silipino, Shadan Hadi, Michèle Weiss-Gayet, Emmanuèle Barras, Christoph D. Schmid, Aouatef Ait-Lounis, Ashley Barnes, Yang Song, David J. Eisenman, Efrat Eliyahu, Gregory I. Frolenkov, Scott E. Strome, Bénédicte Durand, Norann A. Zaghloul, Sherri M. Jones, Walter Reith, Ronna Hertzano

Physiology Faculty Publications

Sensorineural hearing loss is a common and currently irreversible disorder, because mammalian hair cells (HCs) do not regenerate and current stem cell and gene delivery protocols result only in immature HC-like cells. Importantly, although the transcriptional regulators of embryonic HC development have been described, little is known about the postnatal regulators of maturating HCs. Here we apply a cell type-specific functional genomic analysis to the transcriptomes of auditory and vestibular sensory epithelia from early postnatal mice. We identify RFX transcription factors as essential and evolutionarily conserved regulators of the HC-specific transcriptomes, and detect Rfx1,2,3,5 and 7 in the developing HCs. …

Enhanced Nmda Receptor-Mediated Modulation Of Excitatory Neurotransmission In The Dorsal Vagal Complex Of Streptozotocin-Treated, Chronically Hyperglycemic Mice, Eva C. Bach, Katalin Cs. Halmos, Bret N. Smith

Physiology Faculty Publications

A variety of metabolic disorders, including complications experienced by diabetic patients, have been linked to altered neural activity in the dorsal vagal complex. This study tested the hypothesis that augmentation of N-Methyl-D-Aspartate (NMDA) receptor-mediated responses in the vagal complex contributes to increased glutamate release in the dorsal motor nucleus of the vagus nerve (DMV) in mice with streptozotocin-induced chronic hyperglycemia (i.e., hyperglycemic mice), a model of type 1 diabetes. Antagonism of NMDA receptors with AP-5 (100 μM) suppressed sEPSC frequency in vagal motor neurons recorded in vitro, confirming that constitutively active NMDA receptors regulate glutamate release in the DMV. There …

Smooth-Muscle Bmal1 Participates In Blood Pressure Circadian Rhythm Regulation, Zhongwen Xie, Wen Su, Shu Liu, Guogang Zhao, Karyn Esser, Elizabeth A. Schroder, Mellani Lefta, Harald M. Stauss, Zhenheng Guo, Ming Cui Gong

Physiology Faculty Publications

As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood …

Cannabinoid Receptor 2 Agonist Attenuates Pain Related Behavior In Rats With Chronic Alcohol/High Fat Diet Induced Pancreatitis, Liping Zhang, Robert H. Kline Iv, Terry A. Mcnearney, Michael P. Johnson, Karin Westlund High

Physiology Faculty Publications

BACKGROUND: Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in …

An Intronic Picalm Polymorphism, Rs588076, Is Associated With Allelic Expression Of A Picalm Isoform, Ishita Parikh, Christopher Medway, Steven Younkin, David Fardo, Steven Estus

Physiology Faculty Publications

BACKGROUND: Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer's disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179.

RESULTS: We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated …

Neutral Sphingomyelinase-3 Mediates Tnf-Stimulated Oxidant Activity In Skeletal Muscle, Jennifer S. Moylan, Jeffrey D. Smith, Erin M. Wolf Horrell, Julie B. Mclean, Gergana M. Deevska, Mark R. Bonnell, Mariana N. Nikolova‑Karakashian, Michael B. Reid

Physiology Faculty Publications

AIMS: Sphingolipid and oxidant signaling affect glucose uptake, atrophy, and force production of skeletal muscle similarly and both are stimulated by tumor necrosis factor (TNF), suggesting a connection between systems. Sphingolipid signaling is initiated by neutral sphingomyelinase (nSMase), a family of agonist-activated effector enzymes. Northern blot analyses suggest that nSMase3 may be a striated muscle-specific nSMase. The present study tested the hypothesis that nSMase3 protein is expressed in skeletal muscle and functions to regulate TNF-stimulated oxidant production.

RESULTS: We demonstrate constitutive nSMase activity in skeletal muscles of healthy mice and humans and in differentiated C2C12 myotubes. nSMase3 ( …

Analgesic Tolerance Of Opioid Agonists In Mutant Mu-Opioid Receptors Expressed In Sensory Neurons Following Intrathecal Plasmid Gene Delivery, Guangwen Li, Fei Ma, Yanping Gu, Li-Yen Mae Huang

Physiology Faculty Publications

Background: Phosphorylation sites in the C-terminus of mu-opioid receptors (MORs) are known to play critical roles in the receptor functions. Our understanding of their participation in opioid analgesia is mostly based on studies of opioid effects on mutant receptors expressed in in vitro preparations, including cell lines, isolated neurons and brain slices. The behavioral consequences of the mutation have not been fully explored due to the complexity in studies of mutant receptors in vivo. To facilitate the determination of the contribution of phosphorylation sites in MOR to opioid-induced analgesic behaviors, we expressed mutant and wild-type human MORs (hMORs) in sensory …

Tricellulin Deficiency Affects Tight Junction Architecture And Cochlear Hair Cells, Gowri Nayak, Sue I. Lee, Rizwan Yousaf, Stephanie E. Edelmann, Claire Trincot, Christina M. Van Itallie, Ghanshyam P. Sinha, Maria Rafeeq, Sherri M. Jones, Inna A. Belyantseva, James M. Anderson, Andrew Forge, Gregory I. Frolenkov, Saima Riazuddin

Physiology Faculty Publications

The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while …

Effect Of Muscle Length On Cross-Bridge Kinetics In Intact Cardiac Trabeculae At Body Temperature, Nima Milani-Nejad, Ying Xu, Jonathan P. Davis, Kenneth S. Campbell, Paul M. L. Janssen

Physiology Faculty Publications

Dynamic force generation in cardiac muscle, which determines cardiac pumping activity, depends on both the number of sarcomeric cross-bridges and on their cycling kinetics. The Frank–Starling mechanism dictates that cardiac force development increases with increasing cardiac muscle length (corresponding to increased ventricular volume). It is, however, unclear to what extent this increase in cardiac muscle length affects the rate of cross-bridge cycling. Previous studies using permeabilized cardiac preparations, sub-physiological temperatures, or both have obtained conflicting results. Here, we developed a protocol that allowed us to reliably and reproducibly measure the rate of tension redevelopment (k_tr; which depends …

Orofacial Neuropathic Pain Mouse Model Induced By Trigeminal Inflammatory Compression (Tic) Of The Infraorbital Nerve, Fei Ma, Liping Zhang, Danielle Lyons, Karin N. Westlund

Physiology Faculty Publications

BACKGROUND: Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC) model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity.

RESULTS: The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild …

Characterization Of Secretory Sphingomyelinase Activity, Lipoprotein Sphingolipid Content And Ldl Aggregation In Ldlr-/- Mice Fed On A High-Fat Diet, Gergana M. Deevska, Manjula Sunkara, Andrew J. Morris, Mariana N. Nikolova‑Karakashian

Physiology Faculty Publications

The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. …

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization In Adult Spinal Cord Neurons, Suzanne Doolen, Camille B. Blake, Bret N. Smith, Bradley K. Taylor

Physiology Faculty Publications

BACKGROUND: Central sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We used Fura-2 AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ to test the hypotheses that: 1. Exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice; 2. Glutamate-evoked Ca2+ mobilization is associated with spontaneous and/or evoked action potentials; 3. Glutamate acts at glutamate receptor subtypes to evoked Ca2+ transients; and 4. The magnitude of glutamate-evoked Ca2+ responses increases in the setting of …

Pegylated Arginine Deiminase Downregulates Colitis In Murine Models, Helieh S. Oz, Jian Zhong, Willem J. S. De Villiers

Physiology Faculty Publications

Arginine deiminase (ADI), an arginine-metabolizing enzyme involved in cell signaling, is dysregulated in multiple inflammatory diseases and cancers. We hypothesized that pegylated ADI (ADI-PEG) provide protection against colitis.

METHODS: Dextran sodium sulfate colitis was induced in IL-10-deficient and BALB/c (WT) mice. ADI-PEG was administered i.p., and inflammatory mediators and pathology were evaluated.

RESULTS: Acute colitis in mice was manifested by increases in inflammatory biomarkers, such as serum amyloid A (SAA, P < 0.001), IL-12 p40, and disease index (3-Fold). In contrast, ADI-PEG significantly decreased clinical disease index, SAA levels, and inflammatory cytokines in blood as well as in colonic explants. Animals developed moderate (2.2 ± 0.3 WT) to severe (3.6 ± 0.5 IL-10 deficient) colonic pathology; and ADI-PEG treatment significantly improved the severity of colitis (P < 0.05). Marked infiltration of CD68+ macrophages and iNOS expression were detected in colonic submucosa in colitic animals but not detected in ADI-PEG-treated animals.

CONCLUSION: ADI-PEG attenuated inflammatory responses by suppression of macrophage infiltration and iNOS expression in colitic animals. ADI-PEG can serve as a potential therapeutic value in IBD.

Age-Associated Disruption Of Molecular Clock Expression In Skeletal Muscle Of The Spontaneously Hypertensive Rat, Mitsunori Miyazaki, Elizabeth Schroder, Stephanie E. Edelmann, Michael E. Hughes, Karl Kornacker, C. William Balke, Karyn A. Esser

Physiology Faculty Publications

It is well known that spontaneously hypertensive rats (SHR) develop muscle pathologies with hypertension and heart failure, though the mechanism remains poorly understood. Woon et al. (2007) linked the circadian clock gene Bmal1 to hypertension and metabolic dysfunction in the SHR. Building on these findings, we compared the expression pattern of several core-clock genes in the gastrocnemius muscle of aged SHR (80 weeks; overt heart failure) compared to aged-matched control WKY strain. Heart failure was associated with marked effects on the expression of Bmal1, Clock and Rora in addition to several non-circadian genes important in regulating skeletal muscle phenotype including …

Functional Plasticity Of Central Trpv1 Receptors In Brainstem Dorsal Vagal Complex Circuits Of Streptozotocin-Treated Hyperglycemic Mice, Andrea Zsombok, Muthu D. Bhaskaran, Hong Gao, Andrei V. Derbenev, Bret N. Smith

Physiology Faculty Publications

Emerging data indicate that central neurons participate in diabetic processes by modulating autonomic output from neurons in the dorsal motor nucleus of the vagus (DMV). We tested the hypothesis that synaptic modulation by transient receptor potential vanilloid type 1 (TRPV1) receptors is reduced in the DMV in slices from a murine model of type 1 diabetes. The TRPV1 agonist capsaicin robustly enhanced glutamate release onto DMV neurons by acting at preterminal receptors in slices from intact mice, but failed to do so in slices from diabetic mice. TRPV1 receptor protein expression in the vagal complex was unaltered. Brief insulin preapplication …

Store-Operated Ca(2+) Entry (Soce) Contributes To Normal Skeletal Muscle Contractility In Young But Not In Aged Skeletal Muscle, Angela M. Thornton, Xiaoli Zhao, Noah Weisleder, Leticia S. Brotto, Sylvain Bougoin, Thomas M. Nosek, Michael B. Reid, Brian Hardin, Zui Pan, Jianjie Ma, Jerome Parness, Marco Brotto

Physiology Faculty Publications

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca(2+) to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca(2+) entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular …

Synaptic Reorganization Of Inhibitory Hilar Interneuron Circuitry After Traumatic Brain Injury In Mice, Robert F. Hunt, Stephen W. Scheff, Bret N. Smith

Physiology Faculty Publications

Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granule cells and excitability of surviving GABAergic hilar interneurons 8–13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found …

Cannabinoid-Mediated Inhibition Of Recurrent Excitatory Circuitry In The Dentate Gyrus In A Mouse Model Of Temporal Lobe Epilepsy, Muthu D. Bhaskaran, Bret N. Smith

Physiology Faculty Publications

Temporal lobe epilepsy (TLE) is a neurological condition associated with neuron loss, axon sprouting, and hippocampal sclerosis, which results in modified synaptic circuitry. Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known. A pilocarpine-induced status epilepticus mouse model of TLE was used to study the effect of cannabinoid agonists on recurrent excitatory circuits of the dentate gyrus using electrophysiological recordings in hippocampal slices isolated from control mice and mice with TLE. Cannabinoid agonists WIN 55,212-2, anandamide (AEA), or 2-arachydonoylglycerol (2-AG) reduced the frequency of spontaneous and tetrodotoxin-resistant excitatory …

Passive Limb Movement Augments Ventilatory Response To Co2 Via Sciatic Inputs In Anesthetized Rats, Jianguo Zhuang, Fadi Xu, Cancan Zhang, Donald T. Frazier

Physiology Faculty Publications

Passive limb movement (PLM) in humans induces a phasic hyperpnea, but the underlying physiological mechanisms remain unclear. We asked whether PLM in anesthetized rats would produce a similar phasic hyperpnea associated with an augmented ventilatory (V̇_E) response to CO₂ that is dependent on sciatic afferents. The animals underwent 5 min threshold PLM, 3 min hypercapnia (5% CO₂), and their combination (CO₂ exposure at the end of 2^nd min of 5-min PLM) before and after bilateral transection of the sciatic nerves. We found that a threshold PLM evoked a phasic hyperpnea, similar to …

Enkephalin-Encoding Herpes Simplex Virus-1 Decreases Inflammation And Hotplate Sensitivity In A Chronic Pancreatitis Model, Hong Yang, Terry A. Mcnearney, Rong Chu, Ying Lu, Yong Ren, David C. Yeomans, Steven P. Wilson, Karin N. Westlund

Physiology Faculty Publications

Background: A chronic pancreatitis model was developed in young male Lewis rats fed a high-fat and alcohol liquid diet beginning at three weeks. The model was used to assess time course and efficacy of a replication defective herpes simplex virus type 1 vector construct delivering human cDNA encoding preproenkephalin (HSV-ENK).

Results: Most surprising was the relative lack of inflammation and tissue disruption after HSV-ENK treatment compared to the histopathology consistent with pancreatitis (inflammatory cell infiltration, edema, acinar cell hypertrophy, fibrosis) present as a result of the high-fat and alcohol diet in controls. The HSV-ENK vector delivered to the pancreatic surface …

The Pulmonary Effects Of Intravenous Adenosine In Asthmatic Subjects, Nausherwan K. Burki, Mahmud Alam, Lu-Yuan Lee

Physiology Faculty Publications

BACKGROUND: We have shown that intravenous adenosine in normal subjects does not cause bronchospasm, but causes dyspnea, most likely by an effect on vagal C fibers in the lungs [Burki et al. J Appl Physiol 2005; 98:180-5]. Since airways inflammation and bronchial hyperreactivity are features of asthma, it is possible that intravenous adenosine may be associated with an increased intensity of dyspnea, and may cause bronchospasm, as noted anecdotally in previous reports.

METHODS: We compared the effects of placebo and 10 mg intravenous adenosine, in 6 normal and 6 asthmatic subjects.

RESULTS: Placebo injection had no significant (p > 0.05) effect …

Fatigue Resistance Of Rat Extraocular Muscles Does Not Depend On Creatine Kinase Activity, Colleen A. Mcmullen, Katrin Hayeß, Francisco H. Andrade

Physiology Faculty Publications

BACKGROUND: Creatine kinase (CK) links phosphocreatine, an energy storage system, to cellular ATPases. CK activity serves as a temporal and spatial buffer for ATP content, particularly in fast-twitch skeletal muscles. The extraocular muscles are notoriously fast and active, suggesting the need for efficient ATP buffering. This study tested the hypotheses that (1) CK isoform expression and activity in rat extraocular muscles would be higher, and (2) the resistance of these muscles to fatigue would depend on CK activity.

RESULTS: We found that mRNA and protein levels for cytosolic and mitochondrial CK isoforms were lower in the extraocular muscles than in …