Identification of ubiquitin ligases required for skeletal muscle atrophy.
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Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy. (+info)
Maturation of muscle properties and its hormonal control in an adult insect.
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The oviposition of female locusts requires longitudinal muscles to tolerate remarkable lengthening. Whether this ability together with concomitant properties develops during maturation or is present throughout life was investigated. The properties of the locust abdominal muscles involved in oviposition behaviour were investigated with respect to their maturation, segment- and gender-specificity and regulation by juvenile hormone (JH). Muscles from the sixth abdominal segment (an oviposition segment) of mature females (>18 days old) were able to tolerate large extensions (>8 mm). At this length, muscles were still able to generate considerable neurally evoked twitch tension. In contrast, muscle fibres from females less than 5 days old did not tolerate extension of more than 4 mm. At this length, tension generation was negligible. The maximum tension generated at different stimulus frequencies was significantly higher in muscles of females more than 18 days old than in females less than 5 days old. Furthermore, the cross-sectional area of muscle fibres increased significantly during reproductive development. Current-clamp recordings from denervated muscle fibres of females more than 18 days old revealed their ability to generate overshooting action potentials. The potentials were tetrodotoxin (TTX)-insensitive (0.5 micromol l(-1) TTX), but were blocked by Cd(2+) (50 micromol l(-1)) or nifedipine (50 micromol l(-1)), which suggests the involvement of L-type Ca(2+) channels. Action potentials recorded from females less than 5 days old differed considerably in amplitude and shape from those recorded from females more than 18 days old, suggesting their maturation during the first 2 weeks of adult life. Inactivation of the corpora allata (CA) by precocene inhibited the maturation of these muscle properties, whereas injection of JH into precocene-treated females reversed this effect. Homologous muscles from the third abdominal segment (a non-oviposition segment, M169) and muscles from males (M214) revealed no comparable changes, although some minor changes occurred during reproductive development. The results suggest a gender- and segment-specific maturation of muscle properties that is related to reproductive behaviour and controlled by JH. (+info)
Adaptive changes in locomotor activity following botulinum toxin injection in ankle extensor muscles of cats.
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The present study investigated the adaptations made in motor behavior following a temporary reduction in ankle extensor activity in the walking cat. Temporary muscle weakness was induced by injecting botulinum toxin into the lateral gastrocnemius (LG), plantaris (PL), and soleus (SOL) muscles, or SOL alone. The medial gastrocnemius (MG) muscle was not injected. Adaptations in the level of muscle activity were recorded using chronically implanted electromyographic (EMG) electrodes. Serial recordings were made prior to botulinum toxin injections and for several days following the injections. Kinematic analysis of ankle joint movements was made from video records to assess the impact of the botulinum toxin injections on the function of the ankle joint during walking. Following injection of the LG, PL, and SOL muscles with botulinum toxin, the amplitude of the MG burst increased over a period of a few days to a week. This increase was similar to the previously reported changes produced in MG following transection of the nerves serving LG, PL, and SOL. Following the weakening of the ankle extensor muscles, there was a temporary deficit in ankle function during walking as evidenced by a marked increase in the amount of ankle flexion that occurred at stance onset. This functional deficit recovered relatively quickly and was not associated with a return of the EMG pattern to the preinjection pattern. After recovery from the initial injections, a second injection of botulinum toxin into SOL alone was performed. No functional deficits were observed in the ankle movements during walking following this second injection. However, weakening SOL produced increases in the burst amplitudes of the MG, LG, and PL muscles over a period of a few days. This suggests that normal movements at the ankle during walking can be generated with more than one pattern of ankle extensor activity and that there is flexibility in how the necessary torque is produced. A final procedure, transection of the nerves serving LG, PL, and SOL, failed to produce any functional deficits in ankle movements. The implication is that adaptations to the neural control of ankle extensor activity that were induced by the initial procedure persisted after the recovery of the injected muscles and were sufficient to compensate for the subsequent challenges. (+info)
Modelling the biomechanics and control of sphincters.
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This paper reviews current mathematical models of sphincters and compares them with a new spatial neuromuscular control model based on known physiological properties. Almost all the sphincter models reviewed were constructed as a component of a more extensive model designed to mirror the overall behaviour of a larger system such as the lower urinary tract. This implied less detailed modelling of the sphincter component. It is concluded that current sphincter models are not suitable for mimicking detailed interactions between a neural controller and a sphincter. We therefore outline a new integrated model of the biomechanics and neural control of a sphincter. The muscle is represented as a lumped-mass model, providing the possibility of applying two- or three-dimensional modelling strategies. The neural network is a multi-compartment model that provides neural control signals at the level of action potentials. The integrated model was used to simulate a uniformly activated sphincter and a partially deficient innervation of the sphincter, resulting in a non-uniformly activated sphincter muscle. During the simulation, the pressure in the sphincter lumen was prescribed to increase sinusoidally to a value of 60 kPa. In the uniformly activated situation, the sphincter muscle remains closed, whereas the partially denervated sphincter is stretched open, although the muscle is intact. (+info)
Influence of activity on the passive electrical properties of denervated soleus muscle fibres in the rat.
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The technique of direct electrical stimulation of denervated muscle was used to study the role of muscle activity per se in controlling the passive electrical properties of muscle fibres. 2. Specific membrane resistance and capacitance of the denervated and the denervated-stimulated muscle fibres were measured by a sinewave technique at frequencies between 5 and 240 Hz. The parameter values were constant at low frequencies up to a variable transition frequency and declined rapidly at higher frequencies. 3. Following denervation the low-frequency value of specific membrane resistance increased (2291 omega cm2 for 19-day denervated fibres vs. 766 omega cm2 for innervated fibres), the specific membrane capacitance declined (2-7 muF/cm2 vs. 3-6 muF/cm2) and the transition frequency shifted towards lower frequencies. The specific internal resistance was higher in denervated fibres (301 omega cm for 19-day denervated fibres vs. 240 omega cm in innervated fibres) apart from a transient decline after 5 days of denervation (164 omega cm). 4. Direct electrical stimulation for 2 weeks beginning on the 5th day after denervation restored all parameters listed above to their original values before denervation. 5. Stimulation arrested in most cases further atrophy from the time of stimulation but did not restore normal fibre size. (+info)
Electrical stimulation of a denervated muscle promotes selective reinnervation by native over foreign motoneurons.
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The effect of electrical stimulation of the denervated posterior cricoarytenoid (PCA) muscle on its subsequent reinnervation was explored in the canine. Eight animals were implanted with a planar array of 36 electrodes for chronic stimulation and recording of spontaneous and evoked electromyographic (EMG) potentials across the entire fan-shaped surface of a muscle pair. Normative EMG data were recorded from each electrode site before unilateral nerve section, and from the innervated partner after nerve section. After randomizing the animals to experimental and control groups, the right recurrent laryngeal nerve innervating the PCA abductor muscle and its adductor antagonists was sectioned and reanastomosed. The PCA muscle in four experimental animals was continuously stimulated during the 11-mo experiment, using a 1-s, 30-pps, biphasic pulse train composed of 1-ms pulses 2-6 mA in amplitude and repeated every 10 s. The remaining four animals served as nonstimulated controls. Appropriate reinnervation by native inspiratory motoneurons was indexed behaviorally by the magnitude of vocal fold opening and electromyographically by the potential across all electrode sites. Inappropriate reinnervation by foreign adductor motoneurons was quantitated by recording EMG potentials evoked reflexly by stimulation of sensory afferents of the laryngeal mucosa. All four experimental animals showed a greater level of correct PCA muscle reinnervation (P < 0.0064) and a lesser level of incorrect reinnervation (P < 0.0084) than the controls. Direct muscle stimulation also appeared to enhance the overall magnitude of reinnervation, but the effect was not as strong (P < 0.113). These findings are consistent with a previous report and suggest that stimulation of a mammalian muscle may profoundly affect its receptivity to reinnervation by a particular motoneuron type. (+info)
An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles.
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We analyzed the formation of neuromuscular junctions (NMJs) in individual muscles of the mouse embryo. Skeletal muscles can be assigned to one of two distinct classes of muscles, termed "Fast Synapsing" (FaSyn) and "Delayed Synapsing" (DeSyn) muscles, which differ significantly with respect to the initial focal clustering of postsynaptic AChRs, the timing of presynaptic maturation, and the maintenance of NMJs in young adult mice. Differences between classes were intrinsic to the muscles and manifested in the absence of innervation or agrin. Paralysis or denervation of young adult muscles resulted in disassembly of AChR clusters on DeSyn muscles, whereas those on FaSyn muscles were preserved. Our results show that postsynaptic differentiation processes intrinsic to FaSyn and DeSyn muscles influence the formation of NMJs during development and their maintenance in the adult. (+info)
Further studies on the control of ACh sensitivity by muscle activity in the rat.
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1. Denervated rat soleus muscles were stimulated directly through chronically implanted electrodes and the influence of different amounts and patterns of stimuli on the acetylcholine (ACh) sensitivity of the muscle was studied. The number of stimuli was varied by giving similar trains of stimuli (10 Hz for 10 sec) at different intervals (0 to 12 hr). The pattern of stimulation was varied by giving different trains of stimuli (100 Hz for 1 sec, 10 Hz for 10 sec and 1 Hz continuously) as the same average frequency of stimulation (1 Hz). 2. Stimulation usually started 5 days after the denervation when ACh hypersensitivity was fully developed. Most stimulation procedures reduced extrajunctional ACh sensitivity to normal or below normal values within 5-21 days, and these levels were maintained on prolonged stimulation. 3. The rate at which ACh hypersensitivity disappeared increased with increasing amount and frequency of stimulation. However, as few as 100 stimuli given every 5-5 hr for 3 weeks caused a tenfold reduction of sensitivity. 4. The stimulation had little or no effect on the ACh sensitivity at the end plate. Along the rest of the fibre the sensitivity was reduced at approximately the same rate except near the tendons where it appeared to fall more slowly in some fibres. 5. The stimulation restored the resting membrane potential of the denervated fibres to normal. (+info)