Increased metabolism of infused 1-methylxanthine by working muscle

Exogenous substrates for capillary endothelial enzymes have potential as markers for changes in capillary recruitment (albeit nutritive flow). The metabolism of infused 1-methylxanthine (1-MX) to 1-methylurate (1-MU) by capillary endothelial xanthine oxidase of the constant-flow perfused rat hindlimb was shown previously to decrease with oxygen uptake (V˙O ₂) when nutritive flow was decreased. In the present study, the metabolism of 1-MX was investigated under conditions when V˙O ₂ and nutritive flow are known to increase during muscle contraction. The constant-flow red blood cell-perfused rat hindlimb at 37 °C was used with sciatic nerve stimulation, and perfusate samples from whole hindlimb and working muscles taken for analysis of oxygen, lactate, 1-MX and 1-MU. Flow to muscle was assessed separately using fluorescent microspheres and was found to increase 2.3-fold to the working muscles while flow to the non-working leg muscles decreased to compensate. The activity of xanthine oxidase of whole muscle extracts was not altered by contraction. Samples from the vein draining the working muscles, and microsphere measurements of flow, indicated increased V˙O ₂ (5.5-fold to 249.2 ± 43.1 μmol h^?1 g^?1, P < 0.001), and 1-MX conversion (2.5-fold to 1.87 ± 0.25 μmol h^?1 g^?1, P < 0.01) (SEM are shown). It is concluded that as 1-MX metabolism parallels V˙O ₂, this substrate may be a useful indicator of changes in capillary (nutritive) surface area in muscle.     

Increased calcium uptake by muscle mitochondria of cold-acclimated rats.

Skeletal muscle mitochondria of cold-acclimated rats have an altered morphology that is related to the occurrence of nonshivering thermogenesis. The transport of calcium by these mitochondria was studied in a search for an alteration in an energy-dissipating mechanism which might be related to the altered morphology and to the altered mode of thermogenesis in the cold-acclimated animal. The rates of calcium uptake, of calcium-stimulated respiration, and of state 4 respiration after calcium uptake were increased in the altered mitochondria. The capacity to accumulate calcium without phosphate was increased, whereas with phosphate all the calcium was removed from the medium and no difference in total uptake was seen. Spontaneous release of calcium was greater but sodium-induced release was unchanged. No effect of cyclic AMP or prostaglandin E1 on release of calcium was seen. The increase in rate of calcium uptake occurred gradually during the first 3-5 wk of acclimation to cold. The results are considered to give some support to the hypothesis that adaptive changes in the mitochondrial calcium transport cycle in skeletal muscle occur during acclimation to cold.     

Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb

The effect of serotonin (5-HT) on the metabolism of infused 1-methylxanthine (1-MX), a putative substrate of capillary endothelial xanthine oxidase (XO), and on the distribution of infused fluorescent microspheres (15 μm) by the artificially constant-flow perfused rat hindlimb preparation was investigated. 1-MX (5–100 μM ) caused a slight inhibition of oxygen uptake (V˙O ₂) but was not vasoactive, either alone or with 5-HT. 1-MX was converted to 1-methylurate (1-MU) and this conversion was inhibited by allopurinol and xanthine. 5-HT (0.35 μM ), which caused vasoconstriction and decreased V˙O ₂, also inhibited the conversion of 1-MX, indicated by a lowered venous perfusate steady-state 1-MU:1-MX ratio from 1.14 ± 0.02 to 0.71 ± 0.02 (P < 0.001), which is equivalent to the rate of conversion decreasing from 0.83 ± 0.03 to 0.63 ± 0.05 nmol min^?1 g^?1. This change closely followed the time course for changes in V˙O ₂ and perfusion pressure and all three changes reversed in parallel when 5-HT was removed. Recoveries of 1-MU plus 1-MX at all times were high (100 ± 5%). 5-HT did not act to inhibit XO. When compared with vehicle alone, 5-HT had either no effect (plantaris, gastrocnemius white, tibialis, extensor digitorum longus, vastus and thigh), or increased microsphere content (soleus and gastrocnemius red, P < 0.05) of muscles with only bone showing a significant decrease (P < 0.05). Since 5-HT did not inhibit XO or alter the net flow to individual muscles in this constant-flow model, the inhibition of conversion of 1-MX to 1-MU is concluded to be the result of a 5-HT-mediated decrease in the access of 1-MX to capillary XO within individual muscles. Possibilities include the redirection of flow to capillaries either in muscle or in connective tissue closely associated with muscle, where resistance is low and effective surface area is less. 1-MX has potential as a marker for muscle nutritive flow.     

Effect of 3-isobutyl-1-methylxanthine on histamine-stimulated gastric secretion in dogs

The effect of IMX on histamine-stimulated gastric secretion has been studied in dogs equipped with gastric cannulas. After determining the histamine dose response, IMX, histamine, and IMX plus histamine were given by a constant intravenous infusion for 3 h, and acid was collected at 15-min intervals. In a separate series of experiments a single dose of 100 mg of db-cAMP was given 1 h after initiation of infusion of IMX, histamine, and histamine plus IMX. Results show that IMX, a potent inhibitor of phosphodiesterase, is a weak stimulant of acid secretion, and augments histamine-stimulated secretion. However, during stimulated acid secretion, there were no significant changes in tissue cAMP levels. Administration of exogenous dib-cAMP did not produce any significant changes in acid secretion in dogs, but did contribute to elevated cAMP levels.     

Increased IGF-1 in muscle modulates the phenotype of severe SMA mice

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.     

Control of energy metabolism in fish white muscle.

Concentrations of key metabolites were determined in carp white muscle before exercise and after maximal activity. It was found that the concentration of ATP decreases by about 65%, ADP decreases slightly, and AMP remains unchanged. Consequently, the level of the free adenylate pool decreases. Simultaneously there is an increase in the concentration of IMP and NH4+. The increase in IMP level and the decrease in adenylate pool are essentially in 1:1 stoichiometry, a result showing that the adenylate pool is decreased by the reaction catalyzed by 5'-AMP deaminase (EC 3.5.4.6.). During exercise there is an increase in levels of glucose-6-phosphate, fructose 6-phosphate, and fructose 1,6-diphosphate that, along with the decrease in ATP levels, can account for the increase in glycolytic flux by activation of phosphofructokinase and pyruvate kinase.     

Increased prefrontal and parietal activity after training of working memory

Working memory capacity has traditionally been thought to be constant. Recent studies, however, suggest that working memory can be improved by training. In this study, we have investigated the changes in brain activity that are induced by working memory training. Two experiments were carried out in which healthy, adult human subjects practiced working memory tasks for 5 weeks. Brain activity was measured with functional magnetic resonance imaging (fMRI) before, during and after training. After training, brain activity that was related to working memory increased in the middle frontal gyrus and superior and inferior parietal cortices. The changes in cortical activity could be evidence of training-induced plasticity in the neural systems that underlie working memory.     

利用生物电阻抗法研究进藏工作的汉族人群骨骼肌含量

目的 探讨进藏工作汉族成年人群和辽宁汉族成年人群骨骼肌含量分布的特点及差异.方法 随机抽取进藏工作的辽宁本地汉族、辽宁汉族健康成人作为研究对象,共选取进藏辽宁本地汉族成人223名(男95,女128);辽宁汉族成人302名(男126,女176),应用体成分分析仪对受试者的体重、全身肌肉量、躯干肌肉量、左上肢肌肉量、右上肢...     

Increased oxidative metabolism in PMA-activated lymphocytes: a flow cytometric study.

Flow cytometry and the fluorescent dyes DCF and R123 were used to examine oxygen metabolite production in human leukocytes and T-lymphoblastoid Jurkat cells, activated by PMA or by FMLP. When unseparated leukocytes were activated by PMA, oxidative products were generated not only in PMN and monocytes but also to a lower extent in lymphocytes. These responses were correlated with protein kinase C activation. PMA did not, however, induce the synthesis of reactive oxygen species in isolated lymphocytes. FMLP did not affect lymphocyte oxidative metabolism when added to the whole leukocyte mixture, but activated only the phagocyte populations. Similarly, Jurkat cells which alone were unresponsive to PMA, became strongly fluorescent when they were mixed with PMN and treated with this activator. In all cases, they did not respond to FMLP. Superoxide dismutase and catalase addition did not prevent the lymphoid cell response in the presence of phagocytes, whereas Desferal did. These data indicate that under physiological conditions, activated lymphocytes are capable of oxidative metabolism and also evidence some close relation between the leukocyte populations. We discuss the putative mechanism of oxygen metabolite generation in lymphocytes and the role of these metabolites in the immune response.