Immobilization depresses insulin signaling in skeletal muscle.
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Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways. (+info)
Decline after immobilisation and recovery after remobilisation of synovial fluid IL1, TIMP, and chondroitin sulphate levels in young beagle dogs.
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OBJECTIVE: To monitor the concentration of markers of cartilage and synovium metabolism in the knee (stifle) joint synovial fluid of young beagles subjected to immobilisation and subsequent remobilisation. METHODS: The right hind limb of 17 dogs was immobilised in flexion for 11 weeks. Simultaneously, the contralateral left knee was exposed to increased weight bearing. The remobilisation period lasted 50 weeks. Litter mates served as controls. The concentration in joint lavage fluid of interleukin 1alpha (IL1alpha) was measured by immunoassay, the activity of phospholipase A(2) (PLA(2)) was determined by an extraction method, chondroitin sulphate (CS) concentration by precipitation with Alcian blue, hyaluronan (HA) by an ELISA-like assay using biotinylated HA-binding complexes, matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinases 1 (TIMP-1) by sandwich ELISA, and synovitis was scored by light microscopy. RESULTS: Synovitis or effusion was absent in all experimental and control groups. Immobilisation decreased the joint lavage fluid levels of IL1alpha (p<0.05), TIMP (p< 0.05), and the concentration of CS down to 38% (p<0.05) in comparison with untreated litter mates with normal weight bearing. Immobilisation did not affect the activity of PLA(2), or the concentration of MMP-3 or HA in synovial fluid. Joint remobilisation restored the decreased concentrations of markers to control levels. Increased weight bearing did not change the concentrations of markers in comparison with the control joints with normal weight bearing. CONCLUSIONS: 11 weeks' joint immobilisation decreased the concentration of markers of cartilage and synovium metabolism in the synovial fluid, and remobilisation restored the concentrations to control levels. The changes in joint metabolism induced by immobilisation, as reflected by the markers, are thus different from those found in osteoarthritis, where increased levels of these markers are associated with enhanced degradation and synthesis. These findings suggest that the change induced in joint metabolism by immobilisation is reversible in its early stages. (+info)
Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization.
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The purpose of this study was to investigate the effect of oral creatine supplementation on muscle GLUT4 protein content and total creatine and glycogen content during muscle disuse and subsequent training. A double-blind placebo-controlled trial was performed with 22 young healthy volunteers. The right leg of each subject was immobilized using a cast for 2 weeks, after which subjects participated in a 10-week heavy resistance training program involving the knee-extensor muscles (three sessions per week). Half of the subjects received creatine monohydrate supplements (20 g daily during the immobilization period and 15 and 5 g daily during the first 3 and the last 7 weeks of rehabilitation training, respectively), whereas the other 11 subjects ingested placebo (maltodextrine). Muscle GLUT4 protein content and glycogen and total creatine concentrations were assayed in needle biopsy samples from the vastus lateralis muscle before and after immobilization and after 3 and 10 weeks of training. Immobilization decreased GLUT4 in the placebo group (-20%, P < 0.05), but not in the creatine group (+9% NS). Glycogen and total creatine were unchanged in both groups during the immobilization period. In the placebo group, during training, GLUT4 was normalized, and glycogen and total creatine were stable. Conversely, in the creatine group, GLUT4 increased by approximately 40% (P < 0.05) during rehabilitation. Muscle glycogen and total creatine levels were higher in the creatine group after 3 weeks of rehabilitation (P < 0.05), but not after 10 weeks of rehabilitation. We concluded that 1) oral creatine supplementation offsets the decline in muscle GLUT4 protein content that occurs during immobilization, and 2) oral creatine supplementation increases GLUT4 protein content during subsequent rehabilitation training in healthy subjects. (+info)
Effects of joint immobilization on firing rate modulation of human motor units.
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We investigated the effects of 6 weeks of immobilization on firing rate modulation in motor units in the first dorsal interosseous (FDI) of human volunteers. The middle finger, index finger and thumb were immobilized for a period of 6 weeks in a fibre-glass cast, which kept FDI in a shortened position. During isometric contraction at 20, 40, 60 and 80 % of maximal voluntary contraction (MVC) (index finger abduction), motor unit action potentials were recorded from the FDI using a tungsten microelectrode, and the relationship between voluntary force and mean firing rate (MFR) was obtained by plotting the MFR of each motor unit action potential train as a function of voluntary force. Four recording sessions were held for each subject: before immobilization, after 3 and 6 weeks of immobilization, and after a 6 week recovery period. As a result of immobilization, FDI volume (as measured by computerized tomography (CT) scanning) decreased, with an accompanying reduction in aggregate EMG activity per day (P < 0.01). The force measured during MVC also decreased (P < 0.05). The slope of the relationship between voluntary force and MFR was significantly decreased after immobilization, as was the range of firing rate modulation (P < 0.01). Maximal MFR, estimated from the relationship between voluntary force and MFR, was decreased (P < 0.05). MFR was also plotted against voluntary force without being normalized with respect to MVC, and the slope of the regression line was decreased (P < 0.05). Voluntary force when the MFR was 15 Hz was estimated from regression equations for the absolute force-MFR relationship, and it was increased after immobilization (P < 0.05). These results suggest that firing rate modulation shows two different adaptations to joint immobilization: a restriction of motoneurone firing to the lower rates and an enhancement of the voluntary force exerted when the MFR is relatively low. (+info)
Alterations in contractile properties of human skeletal muscle induced by joint immobilization.
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The effects of joint immobilization on the contractile properties of human skeletal muscle were examined using the first dorsal interosseous (FDI) muscle. The middle finger, index finger and thumb were immobilized for a period of 6 weeks, and the contractile properties of FDI were tested before immobilization, after 3 and 6 weeks of immobilization, and after a 6 week recovery period. Twitch and tetanic contractions of FDI were evoked by per-cutaneous electrical stimulation. The peak twitch tension (Pt), contraction time (CT) and half-relaxation time (1/2RT) were measured from twitch contractions, while the stimulus frequency-force relationship was obtained from the tetanic contractions (2 s) evoked using various frequencies of stimulation (10-100 Hz). The fatigability of FDI was tested using Burke's fatigue protocol.Pt was significantly increased after 6 weeks of immobilization (P < 0.05) but little alteration was observed in CT or 1/2RT. No change was noted in the FDI fatigue index throughout the immobilization period. The stimulus frequency-force relationship was shifted to the left by immobilization, indicating that a larger percentage of maximal force was evoked by the lower rates of stimulation. Indeed, the tetanic force evoked by a stimulus frequency of 10 Hz was enhanced after immobilization (P < 0.05). On the other hand, the force evoked by frequencies above 50 Hz, including maximal tetanic tension, was decreased (P < 0.05). As a result, the twitch/tetanus ratio was increased (P < 0.01) after immobilization. The changes induced by immobilization in the FDI twitch/tetanus ratio and the estimated maximal firing rate of FDI motoneurones showed a significant correlation (r = 0.80, P < 0.05). It is suggested that the changes in the contractile properties of the FDI muscle seen after joint immobilization are causally linked to the changes in firing rate modulation of FDI motoneurones. (+info)
Endogenous opiate analgesia induced by tonic immobility in guinea pigs.
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A function of the endogenous analgesic system is to prevent recuperative behaviors generated by tissue damage, thus preventing the emission of species-specific defensive behaviors. Activation of intrinsic nociception is fundamental for the maintenance of the behavioral strategy adopted. Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. We studied the effect of TI behavior on nociception produced by the formalin and hot-plate tests in guinea pigs. The induction of TI produced a significant decrease in the number of flinches (18 +/- 6 and 2 +/- 1 in phases 1 and 2) and lickings (6 +/- 2 and 1 +/- 1 in phases 1 and 2) in the formalin test when compared with control (75 +/- 13 and 22 +/- 6 flinches in phases 1 and 2; 28 +/- 7 and 17 +/- 7 lickings in phases 1 and 2). In the hot-plate test our results also showed antinociceptive effects of TI, with an increase in the index of analgesia 30 and 45 min after the induction of TI (0.67 +/- 0.1 and 0.53 +/- 0.13, respectively) when compared with control (-0.10 +/- 0.08 at 30 min and -0.09 +/- 0.09 at 45 min). These effects were reversed by pretreatment with naloxone (1 mg/kg, ip), suggesting that the hypoalgesia observed after induction of TI behavior, as evaluated by the algesimetric formalin and hot-plate tests, is due to activation of endogenous analgesic mechanisms involving opioid synapses. (+info)
Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain.
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Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. We have previously demonstrated that chronic stress induced an increase in nitric oxide (NO) production via an expression of inducible NO synthase (iNOS) in brain. Since it has been demonstrated that NO regulates mitochondrial function, we sought to study the susceptibility of the mitochondrial respiratory chain complexes to chronic restrain stress exposure in brain cortex. In adult male rats, stress (immobilization for six hours during 21 days) inhibits the activities of the first complexes of the mitochondrial respiratory chain (inhibition of 69% in complex I-III and of 67% in complex II-III), without affecting complex IV activity, ATP production and oxygen consumption. The mitochondrial marker citrate synthase is not significantly affected by stress after 21 days, indicating that at this time the mitochondrial structure is still intact. Moreover, the administration of the preferred inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (400 mg/kg i.p. daily from days 7 to 21 of stress) protects against the inhibition of the activity of complexes of the mitochondrial respiratory chain as well as prevents NO(x)(-) accumulation, lipid peroxidation and glutathione depletion induced by stress. These results suggest that a sustained overproduction of NO via iNOS is responsible, at least in part, of the inhibition of mitochondrial respiratory chain caused by stress and that this pathway also accounts for the oxidative stress found in this situation. (+info)
Plasticity of monkey triceps muscle fibers in microgravity conditions.
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We examined the changes in functional properties of triceps brachii skinned fibers from monkeys flown aboard the BION 11 satellite for 14 days and after ground-based arm immobilization. The composition of myosin heavy chain (MHC) isoforms allowed the identification of pure fibers containing type I (slow) or type IIa (fast) MHC isoforms or hybrid fibers coexpressing predominantly slow (hybrid slow; HS) or fast (hybrid fast) MHC isoforms. The ratio of HS fibers to the whole slow population was higher after flight (28%) than in the control population (7%), and the number of fast fibers was increased (up to 86% in flight vs. 12% in control). Diameters and maximal tensions of slow fibers were decreased after flight. The tension-pCa curves of slow and fast fibers were modified, with a decrease in pCa threshold and an increase in steepness. The proper effect of microgravity was distinguishable from that of immobilization, which induced less marked slow-to-fast transitions (only 59% of fast fibers) and changed the tension-pCa relationships. (+info)