1,721,074 research outputs found
Changes of membrane electrical properties in extensor digitorum longus muscle from dystrophic (mdx) mice
No full textPharmacotherapy of the Lipid-Lowering Drugs: Update on Efficacy and Risk
Full text linkLipid-lowering drugs are widely used for the prevention and cure of cardiovascular diseases (CVD) [...
Pre-clinical trials in Duchenne dystrophy: what animal models can tell us about potential drug effectiveness
No full textThe symptomatic pharmacological therapy of Duchenne dystrophy is poor, glucocorticoids being the sole compounds showing a certain efficacy, although their use is restricted by serious side effects. Pre-clinical trials of prompt-to-use drugs need reliable animal models of the human disease to predict drug effectiveness in patients. The exercised mdx mouse develops a typical pattern of muscle weakness in vivo, which has already been used as an index on which to evaluate drug effectiveness. We have demonstrated that the macroscopic conductance to chloride ion, an index of degeneration-regeneration events occurring in mdx mouse muscles, is specifically impaired by a chronic exercise protocol and is sensitive to the action of in vivo administered drugs acting either by stimulating regeneration (insulin-like growth factor-1 and steroids) or by counteracting calcium-induced degeneration or inflammation (Taurine and steroids). The monitoring of conductance to chloride ion also allows the evaluation of false positive compounds, effective on mouse strength in vivo but not at muscle level, and the functional correlation with other cellular parameters
Aging and chloride channel regulation in rat fast-twitch muscle fibres
No full textBy the use of pharmacological tools, we tested the hypothesis that age-related alterations in the regulatory pathways of chloride channels might contribute to the lowered chloride conductance (GCl) found in skeletal muscle of aged rats. The resting GCl of extensor digitorum longus (EDL) muscles from adult rats either young (3-4 months old) or aged (29 months old) was measured by means of computerized intracellular microelectrode recordings. In EDL muscle from 3 to 4-month-old rats, 4-beta-phorbol 12,13-dibutyrate (4-beta-PDB), a direct activator of protein kinase C (PKC), decreased GCl in a concentration-dependent manner. The same effect was exerted by cholera toxin. The effects of both the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activation of PKC accounts for the decrease of GCl. An increase of cytosolic Ca2+ by the ionophore A23187 also significantly decreased GCl by 25%. In EDL muscles from aged rats, 4-beta-PDB was 20-fold more potent in blocking GCl than in muscles from younger controls, and the ionophore blocked GCl by 40%. On the other hand, cholera toxin was ineffective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of the aging process
Growth hormone administration to aged rats improves membrane electrical properties of skeletal muscle fibers
No full textDecreased secretion of growth hormone (GH) during aging may play a role in the impairment of muscle performance. To test this hypothesis we evaluated the effects of a chronic treatment with 150 μg/kg of GH on membrane electrical properties of extensor digitorum longus muscle of 23-month-old Wistar Kyoto female rats. We found that such treatment could partially but significantly reduce the age-related changes of these parameters. Indeed, with respect to untreated age-matched control rats we found a complete restoration of fiber diameter to the adult value, and a partial improvement of membrane resistance and capacitance values. Furthermore, the GH treatment significantly increased the low total membrane conductance characterizing aged muscle fibers. The increase of total membrane conductance was due to a significant increase toward the adult value of chloride conductance. In addition, the muscles from GH-treated aged rats had values of potassium conductance completely restored down to the adult ones. Accordingly, membrane excitability was also significantly improved by the treatment. The same treatment in adult female rats produced a slight but significant increase of both chloride conductance and potassium conductance, whereas in adult male rats we observed only a significant increase of fiber diameter. Our data show that impairment of GH secretion may contribute to the age-related changes of membrane electrical properties of skeletal muscle and support the potential benefit of GH administration to improve muscle performance in aged subjects
Antimyotonic effects of tocainide enantiomers on skeletal muscle fibers of congenitally myotonic goats
No full textTocainide is effective in the symptomatic treatment of myotonic syndromes for its ability to reduce the high frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However, its use is restricted by serious side effects. In spite of its chiral structure, tocainide is clinically used as a racemic mixture. Since the optical isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R(-) and S(+) enantiomers of tocainide, on the abnormal membrane hyperexcitability of external intercostal muscle fibers of congenitally myotonic goats. The excitability parameters were recorded in vitro by means of the standard two-microelectrode current-clamp technique before and after the addition of the compounds. The R(-) enantiomer of tocainide at concentrations as low as 10 microM potently counteracted the abnormal excitability of myotonic fibers, by increasing the threshold current, and decreasing the latency of the action potential and firing capability. Also, this concentration of R-(-) tocainide almost completely abolished the abnormal spontaneous electrical activity occurring in about 70-80% of the myotonic fiber. The S(+) enantiomer was remarkably less potent since up to 100 microM did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of tocainide resides in the R(-) enantiomer suggesting that its clinical use may allow a significant reduction of the doses and possibly of the side effects
Metabolic Pathways and Ion Channels Involved in Skeletal Muscle Atrophy: A Starting Point for Potential Therapeutic Strategies
Full text linkSkeletal muscle tissue has the important function of supporting and defending the organism. It is the largest apparatus in the human body, and its function is important for contraction and movements. In addition, it is involved in the regulation of protein synthesis and degradation. In fact, inhibition of protein synthesis and/or activation of catabolism determines a pathological condition called muscle atrophy. Muscle atrophy is a reduction in muscle mass resulting in a partial or complete loss of function. It has been established that many physiopathological conditions can cause a reduction in muscle mass. Nevertheless, it is not well known the molecular mechanisms and signaling processes causing this dramatic event. There are multiple concomitant processes involved in muscle atrophy. In fact, the gene transcription of some factors, oxidative stress mechanisms, and the alteration of ion transport through specific ion channels may contribute to muscle function impairment. In this review, we focused on the molecular mechanisms responsible for muscle damage and potential drugs to be used to alleviate this disabling condition
Taurine: the appeal of a safe amino acid for skeletal muscle disorders.
Full text linkTaurine is a natural amino acid present as free form in many mammalian tissues and in particular in skeletal muscle. Taurine exerts many physiological functions, including membrane stabilization, osmoregulation and cytoprotective effects, antioxidant and anti-inflammatory actions as well as modulation of intracellular calcium concentration and ion channel function. In addition taurine may control muscle metabolism and gene expression, through yet unclear mechanisms. This review summarizes the effects of taurine on specific muscle targets and pathways as well as its therapeutic potential to restore skeletal muscle function and performance in various pathological conditions. Evidences support the link between alteration of intracellular taurine level in skeletal muscle and different pathophysiological conditions, such as disuse-induced muscle atrophy, muscular dystrophy and/or senescence, reinforcing the interest towards its exogenous supplementation. In addition, taurine treatment can be beneficial to reduce sarcolemmal hyper-excitability in myotonia-related syndromes. Although further studies are necessary to fill the gaps between animals and humans, the benefit of the amino acid appears to be due to its multiple actions on cellular functions while toxicity seems relatively low. Human clinical trials using taurine in various pathologies such as diabetes, cardiovascular and neurological disorders have been performed and may represent a guide-line for designing specific studies in patients of neuromuscular diseases
EFFECTS OF TAURINE DEPLETION ON EXCITATION-CONTRACTION COUPLING AND CL- CONDUCTANCES OF RAT SKELETAL MUSCLE.
No full textThe pharmacological action of taurine on skeletal muscle is to stabilize sarcolemma by increasing macroscopic conductance to Cl- (GCl), whereas a proposed physiological role for the amino acid is to modulate excitation-contraction coupling mechanism via Ca2+ availability. To get insight in the physiological role of taurine in skeletal muscle, the effects of its depletion were evaluated on voltage threshold for mechanical activation and GCl with the two intracellular microelectrode method in 'point' voltage clamp mode and current clamp mode, respectively. The experiments were performed on extensor digitorum longus muscle fibers from rats depleted of taurine by a chronic 4 week treatment with guanidinoethane sulfonate, a known inhibitor of taurine transporter. The treatment significantly modified the mechanical threshold of striated fibers; i.e. at each pulse duration they needed significantly less depolarization to contract and the fitted rheobase voltage was more negative by 10 mV with respect to untreated muscle fibers. In parallel, the treatment with guanidinoethane sulfonate produced a significant 40% lowering of GCl. In vitro application of 60 mM of taurine to such depleted muscles almost completely restored the mechanical threshold and increased GCl even above the value of untreated control. However, in vitro application of 60 mM of either taurine or guanidinoethane sulfonate to untreated control muscles did not cause any change of the mechanical threshold but increased GCl by 40% and 21%, respectively. Furthermore, 100 microM of the S-(-) enantiomer of 2-(p-chlorophenoxy)propionic acid almost fully blocked GCl but did not produce any change in the mechanical threshold of normal muscle fibers. The present results show that the large amount of intracellular taurine plays a role in the excitation-contraction coupling mechanism of striated muscle fibers. This action is independent from any effect involving muscle Cl- channels, but it is likely mediated by the proposed ability of taurine to modulate Ca2+ availability through the interaction with the Ca2+ transporters present on sarcoplasmic reticulum
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