Effects of inhibitors of cell membrane calcium channels on high-frequency fatigue of fast and slow skeletal muscles

This work investigated the role of extracellular Ca2+ influx through cell membrane Ca2+ channels during high-frequency fatigue (HFF) in slow and fast skeletal muscles of mice. The study was performed in both innervated and in 14-day denervated soleus and EDL muscles of CD1 mice (3-month old). Stimulation in nominally Ca2+-free conditions caused a dramatic increase of fatigue in the slow-twitch soleus muscle, while in the presence of high Ca2+ levels (5 mM) fatigue was reduced. In the fast-twitch EDL muscle, HFF was not affected by external calcium levels either way. These results indicate that HFF of soleus muscle is sensitive to the entry of Ca2+. The possible involvement of store-operated Ca2+ channels (SOCs), mechano-sensitive or stretch-activated cation channels (SACs), L-type voltage-gated Ca2+ channels, and of P2X receptors in HFF development of soleus muscle was investigated by using specific inhibitors. Calciseptine, a specific antagonist of the a1C isoform of the DHPR, did not influence the development of HFF. Gadolinium, a blocker of both SACs and SOCs, and a mixture of P2X receptor inhibitors significantly reduced fatigability of soleus muscle. Interestingly, EDL muscle, which is insensitive to extracellular Ca2+ became sensitive after 14 days of denervation.