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Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.

The purpose of this time-course study was to determine whether satellite cell ablation within rat tibialis anterior (TA) muscles exposed to short-term chronic low-frequency stimulation (CLFS) would limit fast-to-slow fibre type transformations. Satellite cells of the left TA were ablated by exposure to gamma-irradiation before 1, 2, 5 or 10 days of CLFS and 1 week later where required. Control groups received only CLFS or a sham operation. Continuous infusion of 5-bromo-2'-deoxyuridine revealed that CLFS first induced an increase in satellite cell proliferation at 1 day, up to a maximum at 10 days over control (mean +/- SEM, 5.7 +/- 0.7 and 20.4 +/- 1.0 versus 1.5 +/- 0.2 mm(-2), respectively, P < 0.007) that was abolished by gamma-irradiation. Myosin heavy chain mRNA, immunohistochemical and sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses revealed CLFS-induced fast-to-slow fibre type transformation began at 5 days and continued at 10 days; in those muscles that were also exposed to gamma-irradiation, attenuation occurred within the fast fibre population, and the final fast-twitch to slow-twitch adaptation did not occur. These findings indicate satellite cells play active and obligatory roles early on in the time course during skeletal muscle fibre type adaptations to CLFS.

Without intervention after spinal cord injury (SCI), paralyzed skeletal muscles undergo myofiber atrophy and slow-to-fast myofiber type transformations. We hypothesized that chronic spasticity-associated neuromuscular activity after SCI would promote recovery from such deleterious changes. We examined segmental tail muscles of chronic spinal rats with long-standing tail spasticity (7 mo after sacral spinal cord transection; older chronic spinals), chronic spinal rats that experienced less spasticity early after injury (young chronic spinals), and rats without spasticity after transection and bilateral deafferentation (spinal isolated). These were compared with tail muscles of age-matched normal rats. Using immunohistochemistry, we observed myofiber distributions of 15.9 +/- 3.5% type I, 18.7 +/- 10.7% type IIA, 60.8 +/- 12.6% type IID(X), and 2.3 +/- 1.3% type IIB (means +/- SD) in young normals, which were not different in older normals. Young chronic spinals demonstrated transformations toward faster myofiber types with decreased type I and increased type IID(X) paralleled by atrophy of all myofiber types compared with young normals. Spinal isolated rats also demonstrated decreased type I myofiber proportions and increased type II myofiber proportions, and severe myofiber atrophy. After 4 mo of complete spasticity (older chronic spinals), myofiber type transformations were reversed, with no significant differences in type I, IIA, IID(X), or IIB proportions compared with age-matched normals. Moreover, after this prolonged spasticity, type I, IIA, and IIB myofibers recovered from atrophy, and type IID(X) myofibers partially recovered. Our results indicate that early after transection or after long-term spinal isolation, relatively inactive tail myofibers atrophy and transform toward faster myofiber types. However, long-term spasticity apparently produces neuromuscular activity that promotes recovery of myofiber types and myofiber sizes.

Paralyzed skeletal muscle sometimes becomes faster and more fatigable after spinal cord injury (SCI) because of reduced activity. However, in some cases, pronounced muscle activity in the form of spasticity (hyperreflexia and hypertonus) occurs after long-term SCI. We hypothesized that this spastic activity may be associated with a reversal back to a slower, less fatigable muscle. In adult rats, a sacral (S2) spinal cord transection was performed, affecting only tail musculature and resulting in chronic tail spasticity beginning 2 wk later and lasting indefinitely. At 8 mo after injury, we examined the contractile properties of the segmental tail muscle in anesthetized spastic rats and in age-matched normal rats. The segmental tail muscle has only a few motor units (<12), which were easily detected with graded nerve stimulation, revealing two clear motor unit twitch durations. The dominant faster unit twitches peaked at 15 ms and ended within 50 ms, whereas the slower unit twitches only peaked at 30-50 ms. With chronic injury, this slow twitch component increased, resulting in a large overall increase (>150%) in the fraction of the peak muscle twitch force remaining at 50 ms. With injury, the peak muscle twitch (evoked with supramaximal stimulation) also increased in its time to peak (+48.9%) and half-rise time (+150.0%), and decreased in its maximum rise (-35.0%) and decay rates (-40.1%). Likewise, after a tetanic stimulation, the tetanus half-fall time increased by 53.8%. Therefore the slow portion of the muscle was enhanced in spastic muscles. Consistent with slowing, posttetanic potentiation was 9.2% lower and the stimulation frequency required to produce half-maximal tetanus decreased 39.0% in chronic spinals. Interestingly, in spastic muscles compared with normal, whole muscle twitch force was 81.1% higher, whereas tetanic force production was 38.1% lower. Hence the twitch-to-tetanus ratio increased 104.0%. Inconsistent with overall slowing, whole spastic muscles were 61.5% more fatigable than normal muscles. Thus contrary to the classical slow-to-fast conversion that is seen after SCI without spasticity, SCI with spasticity is associated with a mixed effect, including a preservation/enhancement of slow properties, but a loss of fatigue resistance.