Skeletal muscle disuse induces fibre type-dependent enhancement of Na+ channel expression

Abstract

Slow-twitch and fast-twitch muscle fibres have specific contractile properties to respond to specific needs. Since sodium current density is higher in fast-twitch than in slow-twitch fibres, sodium channels contribute to the phenotypic feature of myofibres. Phenotype determination is not irreversible: after periods of rat hindlimb unloading (HU), a model of hypogravity, a slow-to-fast transition occurs together with atrophy in the antigravity slow-twitch soleus muscle. Using cell-attached patch-clamp and northern blot analyses, we looked at sodium channel expression in soleus muscles after 1-3 weeks of HU in rats. We found that sodium channels in fast-twitch flexor digitorum brevis muscle fibres, soleus muscle fibres and 1- to 3-week HU soleus muscle fibres showed no difference in unitary conductance, open probability and voltage-dependencies of activation, fast inactivation and slow inactivation. However, muscle disuse increased sodium current density in soleus muscle fibres 2-fold, 2.5-fold and 3-fold after 1, 2 and 3 weeks of HU, respectively. The concentration of mRNA for the skeletal muscle sodium channel alpha subunit increased 2-fold after 1 week of HU but returned to the control level after 3 weeks of HU. In contrast, the concentration of mRNA for the ubiquitous sodium channel beta(1) subunit was unchanged after 1 week and had increased by 30% after 3 weeks of HU. The tetrodotoxin sensitivity of sodium currents in 3-week HU soleus muscles and the lack of mRNA signal for the juvenile skeletal muscle sodium channel alpha subunit excluded denervation in our experiments. The observed increase in sodium current density may reduce the resistance to fatigue of antigravity muscle fibres, an effect that may contribute to muscle impairment in humans after space flight or after long immobilization.

Modulation of motor cortex excitability after upper limb immobilization

“…This finding, which is likely to be related to disuse atrophy, is in accordance with previous experimental reports of skeletal muscle changes after upper-limb immobilization (Desaphy et al, 2001;Seki et al 2001a;2001b).…”

“…Animal studies suggest that sensory impoverishment may determine changes in the organization and size of cortical receptive fields in the somatosensory cortex (Coq and Xerri, 1999;Langlet et al, 1999). The vast majority of studies on the effects of long term immobilization in humans have examined changes in the contractile properties of skeletal muscle (Desaphy et al, 2001;Seki et al, 2001b) or motor units (Seki et al, 2001a). Only two reports to date have documented central motor changes in neurologically normal subjects who wore splints for more than four weeks because of fractures of the wrist (Zanette et al, 1997) or the leg (Liepert et al, 1995).…”

Fiber Types in Mammalian Skeletal Muscles

“…Expression of Nav 1.5 is restricted to immature and denervated muscles (389), while Nav 1.4 is expressed in adult muscles both in slow and fast fibers. Na channel density is two to three times higher in fast than in slow fibers in humans (673) as in other mammals (125,185). This is consistently supported by evidence obtained in electrophysiological studies as well as in saxitonin binding experiments (317).…”

“…Importantly, inactivation, i.e., the transient decrease of Na conductance which follows a change in membrane potential, has two components: slow inactivation has a time constant in the order of 20 -30 s (736), whereas fast inactivation is much faster (time constant in the order of 0.1-1 ms) and occurs at less negative potentials. Comparing fast and slow fibers, fast inactivation acts at potentials less negative in slow (V h1/2 ϾϪ65 mV) than in fast fibers (V h1/2 ϽϪ65 mV), and the same is true for slow inactivation (V s1/2 ϷϪ70 mV in slow and ϷϪ95 mV in fast fibers) (185,671,673). The molecular basis of such kinetic diversity among fiber types is still uncertain since, as stated above, only one isoform of the pore forming ␣ subunit and one isoform of the auxiliary ␤ subunit are expressed in both slow and fast adult skeletal muscle fibers.…”

“…This is consistently supported by evidence obtained in electrophysiological studies as well as in saxitonin binding experiments (317). No difference is detectable in unitary conductance and open probability of single channels from fast and slow fibers (185). Na current density is 3-10 times higher at the border of the endplate than away from it (62, 672), and this uneven distribution is instrumental to increase efficiency of the neuromuscular transmission.…”