tetrodotoxin and Atrophy

We studied the histochemical and in situ contractile changes in a rat ankle extensor, medial gastrocnemius, in which activation of muscle fibres by motoneurones was blocked for 14 days, using the sodium channel blocker tetrodotoxin applied to the sciatic nerve. Muscles were atrophied and showed slower twitch responses, greater fusion at subtetanic frequencies of stimulation, and higher twitch/tetanic ratios. Tetanic force/mm2 of fibre area and fatiguability were unchanged. Type II fibres were more atrophied and showed greater decreases in mitochondrial succinate dehydrogenase activity than type I fibres. The contractile changes resulting from complete disuse do not occur in models in which weight-bearing alone has been removed (space flight, hindlimb suspension), suggesting that the residual motoneurone activity reported in models of weightlessness is sufficient to prevent these responses. Similarly, the finding of a greater type II fibre susceptibility to complete disuse, which differs from the pattern seen in models of weightlessness, suggest that this residual motoneurone activity in the latter influences atrophic responses in a manner that is variable among motor unit types, to produce the reported preferential type I atrophy characteristic of removal of weight-bearing.

Topics: Animals; Atrophy; Electrophysiology; Female; Hindlimb; Histocytochemistry; Mitochondria, Muscle; Motor Neurons; Muscle Contraction; Muscles; Myofibrils; Rats; Rats, Sprague-Dawley; Succinate Dehydrogenase; Tetrodotoxin; Weightlessness

1. Previous reports of the effects of disuse induced by tetrodotoxin (TTX) have demonstrated alterations in muscle function suggesting changes in the quality of contractile proteins. 2. We extended these studies to the effects of TTX-induced disuse on the Ca2+ activation characteristics of myofibrillar ATPase of the rat gastrocnemius. 3. Atrophic responses were as previously reported (St-Pierre, D.M.M. and Gardiner P.F. (1985) Effect of disuse on mammalian fast-twitch muscle: joint fixation compared with neurally applied tetrodotoxin. Exp. Neurol. 90, 635-651; St-Pierre, D.M.M. et al. (1987). Recovery of muscle from tetrodotoxin-induced disuse and the influence of daily exercise; 1. Contractile properties. Exp. Neurol. 98, 472-488.) with a significant decrease in left gastrocnemius weight compared to control (C) (1.25 +/- 0.06 for C vs 0.72 +/- 0.04 for TTX, X +/- SEM, P less than or equal to 0.01). 4. Myofibrillar protein yield (mg/g wet weight) was also depressed (92.8 +/- 4.5 for C vs 70.3 +/- 3.7 for TTX; P less than or equal to 0.01). 5. Maximum ATPase of myofibrils (nmol Pi/mg/min) was decreased (441 +/- 28 for C vs 181 +/- 30 for TTX, P less than or equal to 0.01). 6. Furthermore, the Hill n which reflects the cooperative aspects of Ca2+ activation of the myofibrillar ATPase was depressed (1.58 +/- 0.07 for C vs 1.29 +/- 0.09 for TTX; P less than or equal to 0.01). 7. The results suggest that muscle perturbations resulting from disuse are partially related to changes in the myofibril.

Topics: Adenosine Triphosphatases; Animals; Atrophy; Body Weight; Calcium; Enzyme Activation; Female; Muscles; Myofibrils; Organ Size; Rats; Rats, Inbred Strains; Tetrodotoxin

Large spherical cells of the mammalian anteroventral cochlear nucleus (AVCN) receive direct excitatory input from auditory nerve axons. Trans-synaptic regulation of neuronal cell size and cell number after cochlear ablation has been previously demonstrated in neonates of several vertebrate species, including the gerbil. Such changes may be related to loss of spontaneous or evoked auditory nerve electrical activity or to loss of activity-independent factors. We have developed a method to chronically, yet reversibly, block auditory nerve electrical activity without violating the integrity of the inner ear. Tetrodotoxin (TTX) was embedded in an ethylene-vinyl acetate copolymer resin (Elvax). A small piece of Elvax containing TTX was placed next to the round window membrane, which allowed TTX to diffuse into the inner ear. As a measure of the effectiveness of manipulation, the onset, duration, and magnitude of the auditory threshold shift were measured by the auditory brainstem response. The sound-evoked response was abolished within 10 minutes of placement of TTX on the round window membrane. The duration of threshold shift was dose-dependent and lasted 24-46 hours. Implants of Elvax without TTX did not produce a significant threshold shift. TTX, which blocks voltage-gated sodium channels, did not abolish the potassium-based cochlear microphonic response. The consequence of blocking afferent electrical activity on gerbil AVCN large spherical cells was examined by measuring their cross-sectional area after each of four manipulations: unilateral auditory nerve action potential blockade with TTX; unilateral surgical cochlear ablation; ipsilateral TTX exposure/contralateral cochlear ablation; and unilateral sham operation (Elvax without TTX).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Atrophy; Auditory Pathways; Cell Count; Cochlear Nerve; Gerbillinae; Rhombencephalon; Tetrodotoxin; Vestibulocochlear Nerve