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AMP-activated protein kinase (AMPK) is a key signaling protein in the regulation of skeletal muscle glucose uptake, but its role in mediating contraction-induced glucose transport is still debated. The effect of contraction on glucose transport is impaired in EDL muscle of transgenic mice expressing a kinase-dead, dominant negative form of the AMPK[[alpha].sub.2] subunit (KD-AMPK[[alpha].sub.2] mice). However, maximal force production is reduced in this muscle, raising the possibility that the defect in glucose transport was due to a secondary decrease in force production and not impaired AMPK[[alpha].sub.2] activity. Generation of force-frequency curves revealed that muscle force production is matched between wild-type (WT) and KD-AMPK[[alpha].sub.2] mice at frequencies [less than or equal to] 50 Hz. Moreover, AMPK activation is already maximal at 50 Hz in muscles of WT mice. When EDL muscles from WT mice were stimulated at a frequency of 50 Hz for 2 min (200-ms train, l/s, 30 volts), contraction caused an ~3.5-fold activation of AMPK[[alpha].sub.2] activity and an ~2-fold stimulation of glucose uptake. Conversely, whereas force production was similar in EDL of KD-AMPK[[alpha].sub.2] animals, no effect of contraction was observed on AMPK[[alpha].sub.2] activity, and glucose uptake stimulation was reduced by 50% (P < 0.01) As expected, 5-aminoimidazole-4-carboxamide-1-[beta]-D-ribofuranosyl 5'-monophosphate (AICAR) caused a 2.3-fold stimulation of AMPK[[alpha].sub.2] activity and a 1.7-fold increase in glucose uptake in EDL from WT mice, whereas no effect was detected in muscle from KD-AMPK[[alpha].sub.2] mice. These data demonstrate that AMPK activation is essential for both AICAR and submaximal contraction-induced glucose transport in skeletal muscle but that AMPK-independent mechanisms are also involved. adenosine 5'-monophosphate-activated protein kinase

Transcription factor p53, which was initially associated with cancer, has now emerged as an important regulator of inflammation and extracellular matrix homeostasis, two processes highly relevant to tendon repair. The goal of this study was to evaluate the effect of a p53 transactivation inhibitor, namely, pifithrin-[alpha], on the pathophysiological sequence following collagenase-induced tendon injury. Administration of pifithrin-[alpha] during the inflammatory phase reduced the accumulation of neutrophils and macrophages by 30 and 40%, respectively, on day 3 postinjury. Pifithrin-[alpha] failed to reduce the percentage of apoptotic cells following collagenase injection but delayed functional recovery. In uninjured Achilles tendons, pifithrin-[alpha] increased metalloprotease activity 2.4fold. Accordingly, pifithrin-[alpha] reduced the collagen content in intact tendons as well as in injured tendons 7 days posttrauma compared with placebo. The effect of pifithrin-[alpha] on load to failure and stiffness was also evaluated. The administration of pifithrin-[alpha] during the inflammatory phase did not significantly decrease the functional deficit 3 days posttrauma. More importantly, load to failure and stiffness were significantly decreased in the pifithrin-[alpha] group from day 7 to day 28 compared with placebo. Overall, our results suggest that administration of pifithrin-[alpha] alters the inflammatory process and delays tendon healing. The present findings also support the concept that p53 can regulate extracellular matrix homeostasis in vivo. inflammation; collagen; apoptosis

Muscle impairment occurs rapidly and precedes inflammatory cell accumulation after mechanical loading. Am J Physiol Regulatory Integrative Comp Physiol 282: R351-R357, 2002; 10.1152/ajpregu.00189. 2001.--Modified muscle use can result in muscle atrophy and impairment. We tested whether inflammatory cell concentrations correlate temporally with muscle impairment during modified loading periods. Rat hindlimbs were unloaded for 10 days followed by reloading. The density of neutrophils and ED[1.sup.+] macrophages was significantly increased by 16.5- and 9.8-fold, respectively, after 1 day of reloading. ED[2.sup.+] macrophage concentration was not significantly increased until 3 days of reloading. Maximal isometric tetanic tension ([P.sub.o]; N/[cm.sup.2]) decreased during hindlimb suspension (HS), which was followed by a second drop in [P.sub.o] after 2 h of reloading. This latter loss in muscle force was uncoupled with the significant elevation in muscle inflammatory cell concentrations. Experiments where HS soleus muscles were incubated with caffeine revealed that at least 40% of the [P.sub.o] decrement at 2 h could be associated with a loss of efficiency of the excitation-contraction (E-C) coupling process. These data suggest that an important mechanism for the early loss in force is the inability to activate the contractile machinery likely caused by a failure in the E-C coupling process during the reloading period. rat; macrophage; neutrophil; inflammation; muscle injury

Adaptation to lengthening contractions is independent of voluntary muscle recruitment but relies on inflammation. Am J Physiol Regulatory Integrative Comp Physiol 282: R323-R329, 2002; 10.1152/ajpregu.00339.2001.--Lengthening contractions trigger an adaptive response decreasing the susceptibility to exercise-induced muscle damage (EIMD). We hypothesized that 1) this adaptation can be observed when voluntary muscle recruitment is bypassed and 2) inflammation repression lessens the adaptive response. Rat ankle dorsiflexors were submitted to two bouts of elicited lengthening contractions 14 days apart; in vitro force production and macrophage concentrations were obtained before and 2 days after each bout in rats treated or not for 2 or 7 days with diclofenac. The first bout caused a 45% force deficit in the placebo group vs. 25% in the diclofenac group, whereas the ED[1.sup.+] macrophage concentration increased by 10- and 5-fold, respectively. After the second bout, only diclofenactreated rats (2 or 7 days) presented significant force deficits and increases in ED[1.sup.+] and ED[2.sup.+] macrophage concentrations, but this was more pronounced in the 7-day group. We conclude that adaptation to lengthening contractions does not depend on neural components but is likely mediated by strengthening of muscle structural/cellular elements and that inflammation is important for this process. skeletal muscle; macrophage; repeated bout effect; repair; non-steroidal anti-inflammatory drug

A study conducted on rat skeletal muscle added to the growing body of evidence suggesting that the reported effects of carbonic anhydrase (CA) inhibitors on fatigue resistance and hexosemonophosphate (HSM) accumulation are indeed the direct result of CA III inhibition. Thus, the hypothesis that an active CA III in a type I muscle plays a mediating role in carbohydrate metabolism and could be associated with the controversial glucose-FAA cycle can be more confidently stated.

A study was conducted to determine if carbonic anhydrase (CA) III inhibition could influence muscle pH and glycolytic rate. The results indicate that the accumulation of hexomonophosphates induced by the CA inhibitors was dependent on the combined presence of external glucose and contractile activity. CA III inhibition may enhance the responsitivity of the contraction-induced glucose uptake process.

Lapointe, Benoit M., and Claude H. Cote. Anesthetics can alter subsequent in vitro assessment of contractility in slow and fast skeletal muscles of rat. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R917-R921, 1999.--Anesthetic agents can interfere with measurement of skeletal muscle contractility in vivo or in situ. Data obtained in vitro are however believed to be unaffected by such drugs. Our objective was to compare in vitro contractile measurements of fast- and slow-twitch muscles dissected from rats anesthetized with pentobarbital sodium (PS, 50 mg/kg ip) or with a mixture of ketamine and xylazine (KX, 87.5:12.5 mg/kg ip). The soleus (Sol) and extensor digitorum longus (EDL) muscles were precisely dissected 10 and 20 min after induction of anesthesia and equilibrated for 20 min in vitro before measuring contractile properties. All data obtained from PS rats were comparable with published values obtained under similar conditions. In EDL, maximum tetanic tension (Po) in KX rats was significantly decreased at both times compared with that in PS muscles. In the Sol, only the muscles exposed for 20 min to KX showed a decreased Po. These results clearly emphasize the need for investigators assessing skeletal muscle contractility in vitro to take into account the type of anesthetics used and the time of in vivo exposition to the drug. muscle relaxant; skeletal muscle; tetanic tension

We evaluated whether contractile fatigue of the quadriceps occurs after cycling exercise in patients with chronic obstructive pulmonary disease (COPD) and whether it could contribute to exercise limitation. Eighteen COPD patients performed two constant work-rate cycling exercises up to exhaustion. These tests were preceded by nebulization of placebo or 500 microg of ipratropium bromide. Muscle fatigue was defined as a postexercise reduction in quadriceps twitch force of more than 15% of the resting value. There was an increase in endurance time postipratropium compared with placebo nebulization (440 +/- 244 seconds vs. 322 +/- 188 seconds, p = 0.06). Nine patients developed contractile fatigue after placebo exercise. In these patients, ipratropium did not increase the endurance time (394 +/- 220 seconds with placebo vs. 400 +/- 119 seconds with ipratropium) despite an 11% improvement in FEV1. In the nine patients who did not fatigue after placebo exercise, endurance time increased from 249 +/- 124 seconds with placebo to 479 +/- 298 seconds with ipratropium (p < 0.05). There was a significant correlation between the improvement in endurance time with ipratropium and quadriceps twitch force at 10 minutes after placebo exercise (r = 0.59, p = 0.01). The occurrence of contractile fatigue during exercise may explain why bronchodilation fails to improve exercise tolerance in some COPD patients.