Short chain fatty acids and colon motility in a mouse model of irritable bowel syndrome

Background Irritable bowel syndrome (IBS) is defined as a multifactorial disorder associated with visceral hypersensitivity, altered gut motility and dysfunction of the brain-gut axis. Gut microbiota and its metabolites are proposed as possible etiological factors of IBS. Short chain fatty acids (SCFAs) induce both inhibitory and stimulatory action on colon motility, however, their effects on the IBS model were not investigated. The aim of our study was to investigate the level of SFCAs in feces and their effects on colon motility in a mouse model of IBS. Methods IBS model was induced in mice by intracolonic infusion of 1% acetic acid during the early postnatal period. Mice colon hypersensitivity was assessed by the threshold of the abdominal withdrawal reflex in response to colorectal distention. Colon contractility was studied using proximal colon specimens in isometric conditions. Transit rates were assessed by the pellet propulsion in the isolated colon. Concentrations of SCFAs in feces were measured using gas–liquid chromatography. Results The concentration of SCFAs in feces of IBS model mice was higher compared to the control group. Visceral sensitivity to colorectal distension and colonic transit rate were increased indicating IBS with predominant diarrhea. The frequency and amplitude of spontaneous contractions of proximal colon segments from IBS mice were higher, but carbachol induced contractions were lower compared to control. During acute application of SCFAs (sodium propionate, sodium acetate or butyric acid) dose-dependently (0.5–30 mM) decreased tonic tension, frequency and amplitude of spontaneous and carbachol-evoked contractions. In the mouse IBS group the inhibitory effects SCFAs on spontaneous and carbachol-evoked contractions were less pronounced. At the same time intraluminal administration of butyrate (5 mM) increased the transit rate in the colon of both groups, but its stimulatory effect was more pronounced in mouse IBS model group. Conclusion Our data indicate that the increased transit rate in the mouse IBS model group is associated with a disbalance of activating and inhibiting action of SCFAs due to chronically elevated SCFA levels, which may impact the pathogenesis of IBS with predominant diarrhea syndrome.

Electrically evoked force loss of the knee extensors is equivalent for young and old females and males

Data are scant on sex-related differences for electrically evoked contractions, which assess intrinsic contractile properties while limiting spinal and supraspinal adaptations to mitigate fatigue. Furthermore, the few studies that exist use stimulus frequencies considerably higher than the natural motor unit discharge rate for the target force. The purpose of this study was to compare force loss to electrically evoked contractions at a physiological stimulus frequency among young females (n = 12), young males (n = 12), old females (n = 11), and old males (n = 11). The quadriceps of the dominant leg were fatigued by 3 min of intermittent transcutaneous muscle belly stimulation (15 Hz stimulus train to initially evoke 25% of maximal voluntary force). Impairment of tetanic contractile impulse (area under the curve) did not differ between sexes for young or old adults or between age groups, with a pooled value of 55.2% ± 12.4% control at the end of fatigue. These data contrast with previous findings at 30 Hz, when the quadriceps of females had greater fatigue resistance than males for young and old adults. The present results highlight the impact stimulus frequency has on intrinsic fatigability of muscle; the findings have implications for future fatigue paradigms and treatment approaches when utilizing electrical stimulation for rehabilitation. Novelty Fatigue was not different between sexes with a stimulation frequency comparable to discharge rates during voluntary contractions. These results highlight that stimulus frequency not only influences fatigue development but also between-group differences.

Contribution of Cav1.2 Ca2+ channels and store-operated Ca2+ entry to pig urethral smooth muscle contraction

Urethral smooth muscle (USM) generates tone to prevent urine leakage from the bladder during filling. USM tone has been thought to be a voltage-dependent process, relying on Ca2+ influx via voltage-dependent Ca2+ channels in USM cells, modulated by the activation of Ca2+-activated Cl− channels encoded by Ano1. However, recent findings in the mouse have suggested that USM tone is voltage independent, relying on Ca2+ influx through Orai channels via store-operated Ca2+ entry (SOCE). We explored if this pathway also occurred in the pig using isometric tension recordings of USM tone. Pig USM strips generated myogenic tone, which was nearly abolished by the Cav1.2 channel antagonist nifedipine and the ATP-dependent K+ channel agonist pinacidil. Pig USM tone was reduced by the Orai channel blocker GSK-7975A. Electrical field stimulation (EFS) led to phentolamine-sensitive contractions of USM strips. Contractions of pig USM were also induced by phenylephrine. Phenylephrine-evoked and EFS-evoked contractions of pig USM were reduced by ~50–75% by nifedipine and ~30% by GSK-7975A. Inhibition of Ano1 channels had no effect on tone or EFS-evoked contractions of pig USM. In conclusion, unlike the mouse, pig USM exhibited voltage-dependent tone and agonist/EFS-evoked contractions. Whereas SOCE plays a role in generating tone and agonist/neural-evoked contractions in both species, this dominates in the mouse. Tone and agonist/EFS-evoked contractions of pig USM are the result of Ca2+ influx primarily through Cav1.2 channels, and no evidence was found supporting a role of Ano1 channels in modulating these mechanisms.

The influence of preceding activity and muscle length on voluntary and electrically evoked contractions

Muscle length and preceding activity independently influence rate of torque development (RTD) and electromechanical delay (EMD), but it is unclear whether these parameters interact to optimize RTD and EMD. The purpose of this study was to determine the influence of muscle length and preceding activity on RTD and EMD during voluntary and electrically stimulated (e-stim) contractions. Participants (n = 17, males, 24 ± 3 years) performed isometric knee extensions on a dynamometer. Explosive maximal contractions were performed at 2 knee angles (35° and 100° referenced to a 0° straight leg) without preceding activity (unloaded, UNL) and with preceding activities of 20%, 40%, 60%, and 80% of maximal voluntary contraction (MVC) torque. Absolute and normalized voluntary RTD were slowed with preceding activities ≥40% MVC for long muscle lengths and all preceding activities for short muscle lengths compared with UNL (p < 0.001). Absolute and normalized e-stim RTD were slower with preceding activities ≥40% MVC compared with UNL (p < 0.001) for both muscle lengths. Normalized RTD was faster at short muscle lengths than at long muscle lengths (p < 0.001) for e-stim (∼50%) and voluntary (∼32%) UNL contractions, but this effect was not present for absolute RTD. Muscle length did not affect EMD (p > 0.05). EMD was shorter at 80% MVC compared with UNL (∼35%; p < 0.001) for both muscle lengths during voluntary but not e-stim contractions. While RTD is limited by preceding activity at both muscle lengths, long muscle lengths require greater preceding activity to limit RTD than short muscle lengths, which indicates long muscle lengths may offer a “protective effect” for RTD against preceding activity.

BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity

Elevated levels of brain-derived neurotrophic factor (BDNF) in urine of overactive bladder (OAB) patients support the association of BDNF with OAB symptoms, but the causality is not known. Here, we investigated the functionality of BDNF overexpression in rat bladder following bladder wall transfection of either BDNF or luciferase (luciferase) transgenes (10 µg). One week after transfection, BDNF overexpression in bladder tissue and elevation of urine BDNF levels were observed together with increased transcript of BDNF, its cognate receptors (TrkB and p75NTR), and downstream PLCγ isoforms in bladder. BDNF overexpression can induce the bladder overactivity (BO) phenotype which is demonstrated by the increased voiding pressure and reduced intercontractile interval during transurethral open cystometry under urethane anesthesia. A role for BDNF-mediated enhancement of prejunctional cholinergic transmission in BO is supported by the significant increase in the atropine- and neostigmine-sensitive component of nerve-evoked contractions and upregulation of choline acetyltransferase, vesicular acetylcholine transporter, and transporter Oct2 and -α1 receptors. In addition, higher expression of transient receptor channels (TRPV1 and TRPA1) and pannexin-1 channels in conjunction with elevation of ATP and neurotrophins in bladder and also in L6/S1 dorsal root ganglia together support a role for sensitized afferent nerve terminals in BO. Overall, genomic changes in efferent and afferent neurons of bladder induced by the overexpression of BDNF per se establish a mechanistic link between elevated BDNF levels in urine and dysfunctional voiding observed in animal models and in OAB patients.