The regeneration of adult rat and mouse slow (soleus) and fast (sternomastoid) muscles was examined after the degeneration of myofibers had been achieved by a snake venom cardiotoxin, under experimental conditions devised to spare as far as possible the satellite cells, the nerves, and the blood vessels of the muscles.Three days after the injury, no myosin was detectable in selected portions of the muscles. New myosins of embryonic, neonatal, and adult types started to be synthesized during the following two days. Adult myosins thus appeared more precociously than in development, which implies that the synthesis of myosin isoforms during regeneration does not entirely 'recapitulate' the sequence of myosin transitions observed during normal development.Two weeks after the injury, the isomyosin electrophoretic pattern displayed by regenerated muscles was already the same as that of control muscles; the normal adult pattern was therefore expressed more rapidly in regenerating than in developing muscles.Except for the synthesis of the slow isoform which was generally inhibited in denervated muscles, the same types of myosins were expressed during the early stages of regeneration in denervated as in innervated muscles; long-term denervation prevented however the qualitative and quantitative recovery of the normal myosin pattern.Regeneration of adult muscles is often considered as a recapitulation of the events which normally occur during myogenesis (for review see Plaghki [I]). A few studies have thus suggested that embryonic, neonatal, and adult myosins are successively synthesized during regeneration [2 -41 and display transitions analogous to those occurring during muscle development [5 -121. More recent results obtained after cold injury of chicken muscles [13, 141 indicate however some differences between the isoform transitions occurring in regenerating and in developing muscles.To explore this further, we have characterized the myosin forms which are synthesized in mammalian slow and fast muscles regenerating after injury by a cardiotoxin purified from the venom of Naja mossambica mossambica [15]. As the toxin was shown to spare the innervation of the muscle, we also examined the influence of the motor nerve on the regeneration, by comparing normally innervated muscles and muscles which had been denervated prior to toxin injury.Preliminary results of this work have been reported [16]. MATERIALS AND METHODS Muscle injuryExperiments were performed on adult Wistar rats and Swiss CF mice of about 200 g and 30 g respectively. Animals were anesthetized with chloral hydrate. Muscles (soleus and sternomastoid) were exposed by an incision of the overlying skin and injected with pure cardiotoxin (10 pM in 0.9% NaCl); the muscles were then bathed in the toxin for 5 min, after which they were perfused and washed with Ringer solution [15]. The muscles were removed, for isomyosin analysis, at various intervals, between 24 h and two months after the injury. As cardiotoxin was observed to spare a few myofibers in the deepest ...

Regeneration of several adult rat and mouse skeletal muscles was studied after degeneration of muscle fibers had been obtained by the selective action of the cardiotoxin of Naja mossambica mossambica venom. Experimental conditions were set up to ensure minimal damage to satellite cells and also the nerves and blood vessels of the original muscles. As in the other types of experimental regeneration, the structure of the regenerated muscle appeared in many respects different from that of the normal muscle. Moreover the neuromuscular junctions of 'en plaque' type were transformed to 'en grappe' type junctions. Many ultrastructural abnormalities often displayed by these junctions might be linked, at least partially, to the persistence in the regenerating muscle of the original synaptic basal lamina sheaths and their inductive properties.

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The expression of myosin during postnatal development was studied in a dozen muscles of the rat. All muscles displayed the usual sequential transitions from embryonic to neonatal and to adult isomyosins. However, we observed that these transitions did not take place uniformly. Thus, half-transition times for the appearance of the adult intermediate and fast myosin extended from seven days for diaphragm, the most precocious muscle of all those examined, to 23 days for male rat masseter. Besides the large differences between their half-transition times, we noticed that the transition curves displayed different slopes, covering different periods. Differences between muscles mainly affected the neonatal-to-adult transition rather than the embryonic-to-neonatal transition, since the embryonic-type myosin disappeared from all muscles examined except for one, at about the Same time, by the end of the first week after birth. In addition, the appearance of slow myosin varied for each muscle and did not follow curves parallel to those for intermediate and fast myosins. These results indicate that each muscle of the rat is subjected to a specific program of myosin isoform transitions during postnatal development.

The soleus and gastrocnemius medialis of eight-day-old rabbits were denervated and the effects were examined after fifty-two days by biochemical, cytochemical and mechanical methods. The contralateral soleus exhibited the properties of slow-type muscle, namely a predominance of slowtype myosin isoforms and slow-type oxidative fibers, slow twitch and low maximal velocity for shortening. The contralateral gastrocnemius exhibited the properties of fast-type muscle, namely a predominance of fast-type myosin isoforms and fast-type non-oxidative fibers, fast twitch and high maximal velocity of shortening. Denervation of muscles caused the differentiation of the two muscles towards slow-type muscles. Both denervated soleus and gastrocnemius muscles exhibited a predominance of slow-type myosins (either the normal type, made up of slow heavy and light chains, or the hybrid type, made up of slow heavy and regulatory light chains and fast essential light chains), a predominance of slow-type fibers, and slow mechanical properties. Thus, innervation in rabbit appears to be a determining factor for differentiation into fast-type muscle, but it is not necessary for differentiation into slow-type muscle. This conclusion contradicts the findings of previous studies in rat and thus raises new questions concerning the role of nerves in controlling the expression of myosin isoforms and the differentiation of muscle fibers.The terminal differentiation of skeletal muscles is under the control of both genetic and epigenetic factors, and various different mechanisms are involved in regulating muscle fiber diversity. The determination of fiber type may be modulated by environmental factors, which also account for the plasticity of muscle. Among these factors, innervation appears to play a major role, as indicated by the pioneering Correspondence to A.

Transitions from embryonic and neonatal to adult-type-I1 isomyosins are known to be related to the increase in the thyroid hormone plasma concentration during postnatal development. These transitions have been shown, however, to occur at different times, depending on the muscle, suggesting that each muscle responds differently to the thyroid hormone. We have investigated quantitatively the effects of experimental hypothyroidism and hyperthyroidism on isomyosin transitions from birth until the 45th postnatal day in eight rat muscles : diaphragm, intercostals, gastrocnemius medialis, soleus, plantar muscles of the foot, tongue muscle, levator ani and bulbocavernosus complex, and masseter.Hypothyroidism delayed the isomyosin transitions in all the muscles examined, particularly in the sexually dimorphic muscles (levator ani and bulbocavernosus complex and masseter). However, it did not eventually inhibit isomyosin transitions, indicating that the thyroid hormone was not an absolute requirement for these to occur.Hyperthyroidism had only a slight effect on isomyosin transition in the diaphragm, and accelerated such transitions in the other muscles. The transition curves of all the muscles investigated, except those of the sexually dimorphic muscles, became similar to that of the diaphragm, demonstrating that the various muscles did not display the same sensitivity to the thyroid hormone but were regulated by it in the same way. The isomyosin transitions in the sexually dimorphic muscles remained late in comparison to that in the diaphragm, which suggests a more complex regulation. The effect of hyperthyroidism was not permanent and could be reversed, by interruption of the treatment, to a greater or lesser extent depending on the muscle.In all muscles containing slow-type-I isomyosin, hypothyroidism had no effect on this isomyosin synthesis, whereas hyperthyroidism inhibited it. This inhibition ceased rapidly after the interruption of the treatment.It is now well established that myosin exists under numerous isoforms, which are specific to the muscle type and to its developmental stage (for review, see [l, 21). In slowly contracting muscles, such as the soleus of the rat, slow-type-I isomyosin, which is present very early in development, increases until constituting more than 90% of the total myosin of the adult [3 -51. In rapidly contracting muscles, such as the hind-leg muscles of the rat, embryonic, neonatal, and adulttype-I1 isomyosins are sequentially synthesized [6]. We have recently shown that the chronology of this sequence is highly dependent on the muscle type and that the half-transition ages for the appearance of adult-type-I1 isomyosins varies from 7 days for the diaphragm to 23 days for the masseter [5]. These values were observed in the rat and depended on the mammal species (unpublished work).Myosin expression thus appears to be differentially regulated during development of the various skeletal muscles of the chimique, Universite Paris-Sud, Bit. 433, F-91405 Orsay, France same animal. Besides the fa...

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