Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers.

Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93A) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789M/-) mutant mice), Schwartz-Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz-Jampel syndrome and nerve injury.

Clinical features of Friedreich ataxia.

Friedreich ataxia, the most common hereditary ataxia, affects approximately 1 per 29,000 white individuals. In about 98% of these individuals, it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2%, it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this autosomal recessive condition is usually in the first 2 decades of life. Major clinical features include progressive ataxia, absent lower limb reflexes, upgoing plantar responses, and peripheral sensory neuropathy. The main nonneurological sites of morbidity are the heart, resulting in cardiomyopathy, and the pancreas, resulting in diabetes mellitus. In this review, we provide an overview of the clinical features of Friedreich ataxia and discuss differential diagnoses.

Renal sympathetic neuroeffector function in renovascular and angiotensin II-dependent hypertension in rabbits.

We tested the hypotheses that the gains of specific renal sympathetic neuroeffector mechanisms are altered in secondary hypertension and that the nature of these alterations depends on the precise experimental setting of the kidney. Rabbits were sham operated, or made comparably hypertensive (mean arterial pressure increased 17% to 24%) by clipping the left or right renal artery or by chronic infusion of angiotensin II (20 to 50 ng kg(-1) min(-1) SC). Four to 6 weeks later, under pentobarbital anesthesia, the left renal nerves were sectioned and electrically stimulated at low (0 to 2 Hz) and high (4 to 8 Hz) frequencies. Neurally evoked reductions in total renal blood flow, cortical perfusion, urine flow, and sodium excretion and increases in renal norepinephrine spillover were not significantly greater in kidneys of hypertensive rabbits than normotensive controls. Neurally evoked increases in renal renin release and the slope of the relationship between renin release and norepinephrine spillover were less in kidneys of hypertensive rabbits than normotensive controls. Low-frequency renal nerve stimulation reduced medullary perfusion, which was negatively correlated with renal norepinephrine spillover in kidneys from all 3 groups of hypertensive rabbits but not normotensive controls. Two-hertz stimulation reduced medullary perfusion by 19% in hypertensive rabbits but not in normotensive rabbits. Thus, of all of the renal sympathetic neuroeffector mechanisms studied, only neural control of medullary perfusion was enhanced in these models of secondary hypertension. This effect appears to be mediated postjunctionally, not through enhanced neural norepinephrine release, and may contribute to the development and/or maintenance of hypertension in these models.

Traditional oriental herbal medicine, Bakumondo-to, suppresses vagal neuro-effector transmission in guinea pig trachea.

OBJECTIVE: Bakumondo-to (Maimendong tang) is a traditional oriental herbal medicine that has been used as an antitussive agent. We previously demonstrated that Bakumondo-to attenuates airway hyperresponsiveness induced by ozone. However, the mechanism(s) responsible for this effect remains unclear. In the present study, we examined the mechanism whereby Bakumondo-to inhibits ozone-induced airway hyperresponsiveness. First, we examined the effect of Bakumondo-to on prostanoids production, which are key mediators to airway hyperresponsiveness after ozone exposure. Second, we studied its effects on the vagal neuroeffector transmission, because vagal nerve is likely to play an important role in airway hyperresponsiveness after ozone. METHODS: We measured the effects of Bakumondo-to on the concentrations of prostanoids in bronchoalveolar lavage fluid before and after ozone. We evaluated the effects of Bakumondo-to on the contraction of guinea pig tracheal smooth muscle evoked by electrical field stimulation (EFS) or the exogenous application of acetylcholine (ACh). Isometric tension of tracheal strips was measured in the presence of indomethacin (10(-6) M) and of guanethidine (10(-6) M). RESULTS: Ozone caused significant increase in prostaglandin E2 (PGE2) and thromboxane B2 (TXB2); however, Bakumondo-to did not affect the increase in these prostanoids. Bakumondo-to (0.01 mg/mL-1 mg/mL) significantly suppressed the contraction evoked by EFS, but did not affect the ACh-evoked contraction, indicating that Bakumondo-to suppressed tracheal smooth muscle contraction pre-junctionally. CONCLUSION: These results suggest that the mechanism by which Bakumondo-to inhibits airway hyperresponsiveness depends on inhibiting the release of acetylcholine from vagal nerve terminals.

Effects of vitamin E deficiency on autonomic neuroeffector mechanisms in the rat caecum, vas deferens and urinary bladder.

1. Modified sucrose-gap, standard organ-bath techniques and transmitter release studies were used to examine neuromuscular transmission in the caecum, vas deferens and urinary bladder in normal rats and in rats maintained for 12 months on a diet free of vitamin E. 2. In the caecum circular muscle, non-adrenergic, non-cholinergic inhibitory junction potentials were absent from 48 and 15% of preparations from vitamin E-deficient and control animals, respectively. Cholinergic excitatory junction potentials were absent from 83 and 8% of vitamin E-deficient and control preparations, respectively. Responses to applied noradrenaline (0.1-30 microM), alpha,beta-methylene ATP (3-100 microM) and acetylcholine (0.1-30 microM) were attenuated or absent in vitamin E-deficient tissues. Responses to applied KCl were similar in both groups. Release of [3H]noradrenaline or endogenous acetylcholine could not be evoked from vitamin E-deficient tissues. 3. In contrast, in isolated preparations of the vas deferens and urinary bladder, neuromuscular transmission by adrenergic, cholinergic and purinergic components were unaffected by long-term vitamin E deficiency. 4. In conclusion, vitamin E deficiency causes dysfunction of autonomic neuroeffector mechanisms in the smooth muscle of the rat caecum, at both a pre- and postjunctional level. The lesions in autonomic transmission mechanisms brought about by long-term vitamin E deficiency were found only in the caecum; no changes in sympathetic neuromuscular transmission were observed in the vas deferens, or in parasympathetic neuromuscular transmission in the urinary bladder.

Beta-adrenergic neuroeffector mechanisms in cardiac hypertrophy of renin transgenic rats.

We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2d gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of beta 1-adrenergic receptors, an increase of inhibitory G protein alpha-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein alpha-subunits and beta 2-adrenergic receptors was unchanged. Desensitization of adenylyl cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages.

Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions.

The results of recent investigations designed to elucidate the neuroeffector functions of sensory fibres, the cause of migraine headache and the mechanism of action of antimigraine drugs are reviewed and discussed. Neurogenic inflammation (vasodilatation and neurogenic plasma extravasation) is one explanation for the development of headaches and the blood flow changes which occur during migraine headache. Numerous studies have recently been carried out on rats and guinea-pigs into the effects of antimigraine agents, including ergot alkaloids, sumatriptan and non-steroidal anti-inflammatory drugs (NSAIDs), on neurogenic plasma protein extravasation in the dura mater induced by electrical stimulation of trigeminal ganglia or systemic administration of capsaicin. It is known that the dura mater is able to produce headaches in man. Ergot alkaloids have been shown to block neurogenic inflammation via a C-fibre dependent neuronal mechanism. Sumatriptan appears to act fairly similarly although, whereas the ergot alkaloids are non-selective for either 5-hydroxytryptamine (5-HT; serotonin) receptors or 5-HT1, sumatriptan is selective for 5-HT1 receptors. The antimigraine action of NSAIDs may be via either an effect on blood vessels or an effect on the nerve fibre. The antimigraine effects of ergot alkaloids, sumatriptan and NSAIDs are discussed in the light of the common vasoconstrictor actions of these agents and knowledge that vasodilatation is apparently not responsible for migraine headache pain in most cases.

Vascular neuroeffector mechanisms in hypertension.

Recent studies of the peripheral sympathetic nervous system indicate the presence of other vasoactive transmitters in addition to noradrenaline. There is now evidence suggesting ATP to be a co-transmitter of noradrenaline mediating the excitatory junction potential and the phentolamine-resistant component of the vasopressor response. In hypertension, changes in the neural regulation at both pre- and post-synaptic levels have been observed. In the spontaneously hypertensive rat (SHR), abnormal feedback regulation through presynaptic adrenoceptors and increases in release and uptake by the perivascular nerves are well characterized. Whether similar changes in the ATP release mechanism occur in the SHR and other forms of hypertension remain to be determined. A more important role for ATP in the neural regulation of the SHR tail artery has been proposed. In future studies, the possible contribution of co-transmitters to the responses should be taken into consideration.