Citations

We have previously described a negative feedback loop that inhibits duodenal motility when nutrients are infused into the ileum and colon. In the present study, we examined the role of extrinsic innervation and plasma levels of peptide YY (PYY) in mediating this phenomenon. We perfused neurally intact ( n = 5 dogs) or extrinsically denervated ( n = 6 dogs) isolated loops of proximal colon with isomolar NaCl or a mixed-nutrient solution at 2 and 6 ml/min for 4 h during fasting or for 2 h beginning 15 min after a meal. Both rates of infusion with NaCl prolonged the cycle length of the duodenal migrating motor complex (MMC) in the group with neurally intact loops but not in the group with extrinsically denervated loops. Nutrient infusions increased the MMC cycle length in both groups. Integrated plasma concentrations of PYY were increased by nutrients but not by NaCl in both groups. These data suggest that increased volumes and unabsorbed nutrients in the proximal colon alter proximal small bowel motility. Volume-induced effects are mediated via extrinsic nerves, whereas nutrient-induced effects may be mediated by humoral factors, such as plasma PYY.

To explore mechanisms whereby unabsorbed nutrients in the ileum inhibit the upper gut ("ileal brake"), we perfused the canine ileum or colon and monitored phase 3 in the duodenum. Fasting motility was recorded when the ileum or colon was perfused with 154 mM NaCl, a mixed isotonic nutrient solution (Ensure), or individual nutrients (maltose, casein hydrolysates, or sodium oleate). Blood samples were collected before and during the perfusions. The ileum was also perfused with 154 mM NaCl while peptide YY (PYY) was infused by vein. In both sets of experiments, plasma levels of PYY, neurotensin, and glucagon-like peptide-1 (GLP-1) were measured. Ileal or colonic perfusion of Ensure delayed phase 3 [migrating motor complexes (MMC)] in the duodenum, inhibited ileal motility, and increased plasma levels of PYY and GLP-1. Ileal casein and oleate and colonic casein also delayed the duodenal MMC. The MMC cycle length and plasma levels of PYY were closely correlated. Intravenous PYY prolonged the MMC cycle; an intravenous dose of 100 pmol.kg-1.h-1 of PYY mimicked the effects of ileal Ensure. These results support the hypothesis that PYY, and possibly GLP-1, participate in the ileal brake. This negative feedback loop also affects the distal small bowel. The proximal colon also triggers the feedback inhibition of gut motility (colonic brake).

The effect of chronic exogenous testosterone (T) treatment on neuromuscular transmission in the diaphragm (Dia) muscle of adult male rats was determined. The contribution of neuromuscular transmission failure (NTF) to Dia fatigue was evaluated by superimposing intermittent direct muscle stimulation on repetitive nerve stimulation of isometric contraction in vitro. T treatment significantly reduced the contribution of NTF to Dia fatigue by ∼20% ( P < 0.001). Fiber type-specific effects on NTF were determined by measuring Dia fiber glycogen levels subsequent to repetitive nerve or muscle stimulation. T treatment had no effect on glycogen depletion in Dia type I and IIa fibers regardless of stimulation route. In the control group, type IIx fibers demonstrated significantly less glycogen depletion after nerve stimulation compared with direct muscle stimulation ( P < 0.05), suggesting the presence of NTF. In contrast, T treatment increased glycogen depletion of type IIx fibers during nerve stimulation to levels similar to those after direct muscle stimulation. These data indicate that testosterone treatment substantially improves neuromuscular transmission in the Dia.

We hypothesized that decrements in maximum power output (W˙max) of the rat diaphragm (Dia) muscle with repetitive activation are due to a disproportionate reduction in force (force fatigue) compared with a slowing of shortening velocity (velocity fatigue). Segments of midcostal Dia muscle were mounted in vitro (26°C) and stimulated directly at 75 Hz in 400-ms-duration trains repeated each second (duty cycle = 0.4) for 120 s. A novel technique was used to monitor instantaneous reductions in maximum specific force (Po) andW˙maxduring fatigue. During each stimulus train, activation was isometric for the initial 360 ms during which Powas measured; the muscle was then allowed to shorten at a constant velocity (30% Vmax) for the final 40 ms, and W˙maxwas determined. Compared with initial values, after 120 s of repetitive activation, PoandW˙maxdecreased by 75 and 73%, respectively. Maximum shortening velocity was measured in two ways: by extrapolation of the force-velocity relationship ( Vmax) and using the slack test [maximum unloaded shortening velocity ( Vo)]. After 120 s of repetitive activation, Vmaxslowed by 44%, whereas Voslowed by 22%. Thus the decrease inW˙maxwith repetitive activation was dominated by force fatigue, with velocity fatigue playing a secondary role. On the basis of a greater slowing of Vmaxvs. Vo, we also conclude that force and power fatigue cannot be attributed simply to the total inactivation of the most fatigable fiber types.

We hypothesized that unilateral denervation (DNV) of the rat diaphragm muscle (Diam) in neonates at postnatal day 7 (D-7) alters normal transitions of myosin heavy chain (MHC) isoform expression and thereby affects postnatal changes in maximum specific force (Po) and maximum unloaded shortening velocity ( Vo). The relative expression of different MHC isoforms was analyzed electrophoretically. With DNV at D-7, expression of MHCneoin the Diampersisted, and emergence of MHC2Xand MHC2Bwas delayed. By D-21 and D-28, relative expression of MHC2Aand MHC2Bwas reduced in DNV compared with control (CTL) animals. Expression of MHCneoalso reappeared in adult Diamby 2–3 wk after DNV, and relative expression of MHC2Bwas reduced. At each age, Powas reduced and Vowas slowed by DNV, compared with CTL. In CTL Diam, postnatal changes in Poand Vowere associated with an increase in fast MHC isoform expression. In DNV Diam, no such association existed. We conclude that, in the Diam, DNV induces alterations in both MHC isoform expression and contractile properties, which are not necessarily causally linked.

There is a mediolateral gradient in activation of the parasternal intercostal (PI) muscle during inspiration. In the present study, we tested the hypotheses that serotonergic [5-hydroxytryptamine (5-HT)] input from descending central drive and/or intrinsic size-related properties of PI motoneurons leads to the differential activation of PI muscles. In dogs, PI motoneurons innervating the medial and lateral regions of the PI muscles at the T3–T5interspaces were retrogradely labeled by intramuscular injection of cholera toxin B subunit. After a 10-day survival period, PI motoneurons and 5-HT terminals were visualized by using immunohistochemistry and confocal imaging. There were no differences in motoneuron morphology among motoneurons innervating the medial and lateral regions of the PI muscle. However, the number of 5-HT terminals and the 5-HT terminal density (normalized for surface area) were greater in motoneurons innervating the medial region of the PI muscle compared with the lateral region. These results suggest that differences in distribution of 5-HT input may contribute to regional differences in PI muscle activation during inspiration and that differences in PI motoneuron recruitment do not relate to size.

Swallow, John G., Theodore Garland, Jr., Patrick A. Carter, Wen-Zhi Zhan, and Gary C. Sieck. Effects of voluntary activity and genetic selection on aerobic capacity in house mice ( Mus domesticus). J. Appl. Physiol. 84(1): 69–76, 1998.—An animal model was developed to study effects on components of exercise physiology of both “nature” (10 generations of genetic selection for high voluntary activity on running wheels) and “nurture” (7–8 wk of access or no access to running wheels, beginning at weaning). At the end of the experiment, mice from both wheel-access groups were significantly lighter in body mass than mice from sedentary groups. Within the wheel-access group, a statistically significant, negative relationship existed between activity and final body mass. In measurements of maximum oxygen consumption during forced treadmill exercise (V˙o2 max), mice with wheel access were significantly more cooperative than sedentary mice; however, trial quality was not a significant predictor of individual variation in V˙o2 max. Nested two-way analysis of covariance demonstrated that both genetic selection history and access to wheels had significant positive effects on V˙o2 max. A 12% difference inV˙o2 maxexisted between wheel-access selected mice, which had the highest mass-correctedV˙o2 max, and sedentary control mice, which had the lowest. The respiratory exchange ratio at V˙o2 maxwas also significantly lower in the wheel-access group. Our results suggest the existence of a possible genetic correlation between voluntary activity levels (behavior) and aerobic capacity (physiology).

Van Balkom, Roland H. H., Wen-Zhi Zhan, Y. S. Prakash, P. N. Richard Dekhuijzen, and Gary C. Sieck. Corticosteroid effects on isotonic contractile properties of rat diaphragm muscle. J. Appl. Physiol. 83(4): 1062–1067, 1997.—The effects of corticosteroids (CS) on diaphragm muscle (Diam) fiber morphology and contractile properties were evaluated in three groups of rats: controls (Ctl), surgical sham and weight-matched controls (Sham), and CS-treated (6 mg ⋅ kg−1 ⋅ day−1prednisolone at 2.5 ml/h for 3 wk). In the CS-treated Diam, there was a selective atrophy of type IIx and IIb fibers, compared with a generalized atrophy of all fibers in the Sham group. Maximum isometric force was reduced by 20% in the CS group compared with both Ctl and Sham. Maximum shortening velocity in the CS Diamwas slowed by ∼20% compared with Ctl and Sham. Peak power output of the CS Diam was only 60% of Ctl and 70% of Sham. Endurance to repeated isotonic contractions improved in the CS-treated Diam compared with Ctl. We conclude that the atrophy of type IIx and IIb fibers in the Diam can only partially account for the CS-induced changes in isotonic contractile properties. Other factors such as reduced myofibrillar density or altered cross-bridge cycling kinetics are also likely to contribute to the effects of CS treatment.

The effects of corticosteroid (CS) treatment (prednisolone continuously administered subcutaneously at a flow rate of 2.5 μl/h, daily dose 5.6 mg/kg, for 3 wk) on neuromuscular junction (NMJ) morphology and neuromuscular transmission in rat diaphragm muscle (Dimus) were compared with weight-matched (Sham) and ad libitum fed control (Ctl) groups. Fibers were classified on the basis of myosin heavy chain (MHC) isoform expression. CS treatment caused significant atrophy of fibers expressing MHC2X(type IIx), either alone or with MHC2B(type IIx/b). Fibers expressing MHCslow(type I) and MHC2A(type IIa) were unaffected by CS. The planar areas of nerve terminals and motor endplates at type IIx/b fibers were smaller in CS-treated Dimuscompared with Sham and Ctl. However, CS-induced atrophy of type IIx/b fibers exceeded changes in NMJ morphology. Thus, when normalized for fiber diameter, NMJs were relatively larger in the CS-treated group compared with Ctl. Neuromuscular transmission failure, assessed in vitro by comparing force loss during repetitive (40 Hz) nerve vs. direct muscle stimulation, was less in CS-treated Dimus. These results indicate that alterations in NMJ morphology after CS treatment are dependent on fiber type and may contribute to improved neuromuscular transmission.

Howell, Sandra, Wen-Zhi Zhan, and Gary C. Sieck.Diaphragm disuse reduces Ca2+uptake capacity of sarcoplasmic reticulum. J. Appl. Physiol. 82(1): 164–171, 1997.—Chronic phrenic tetrodotoxin (TTX) blockade and phrenic denervation (Dnv) of hamster diaphragm result in decreased maximum specific tension, prolonged contraction time, and improved fatigue resistance (W. Z. Zhan and G. C. Sieck. J. Appl. Physiol. 72: 1445–1453, 1992). An underlying increased relative contribution of type I fibers to total muscle mass appears to be consistent with, but does not completely account for, changes in contractile and fatigue properties. The present study was designed to evaluate a potential role for altered cellular Ca2+metabolism in the adaptive response of the diaphragm to chronic disuse. An analytic method based on simulation and modeling of long-term45Ca2+efflux data was used to estimate Ca2+ contents (nmol Ca2+/g wet wt tissue) and exchange fluxes (nmol Ca2+ ⋅ min−1 ⋅ g−1) for extracellular and intracellular compartments in the in vitro hamster hemidiaphragm after prolonged disuse. Three groups were compared: control (Con, n = 5), phrenic TTX blockade (TTX, n = 5), and phrenic denervation (Dnv, n = 5). Experimental muscles were loaded with45Ca2+for 1 h, and efflux data were collected for 8 h by using a flow-through tissue chamber. Compartmental analysis of efflux data estimated that the Ca2+ contents and Ca2+ exchange fluxes of the largest and slowest intracellular compartment (putative longitudinal reticulum) were reduced by ∼50% in TTX and Dnv muscle groups compared with Con. In addition, the kinetic model predicted significant decreases in total intracellular Ca2+ and total diaphragm Ca2+ in TTX and Dnv muscles. We conclude that the data support the hypothesis that the capac- ity of the sarcoplasmic reticulum for Ca2+ sequestration is reduced in chronic diaphragm disuse. The impact of this effect on diaphragm contractile and fatigue properties is discussed.