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Eur J Appl Physiol (2008) 104:445453 DOI 10.1007/s00421-008-0796-5
ORIGINAL ARTICLE
High-frequency fatigue of skeletal muscle: role of extracellular Ca2+
Elena Germinario Alessandra Esposito
Menotti Midrio Samantha Peron Philip T. Palade Romeo Betto Daniela Danieli-Betto
Accepted: 3 June 2008 / Published online: 17 June 2008 Springer-Verlag 2008
Abstract The present study evaluated whether Ca2+ entry operates during fatigue of skeletal muscle. The involvement of diVerent skeletal muscle membrane calcium channels and of the Na+/Ca2+ exchanger (NCX) has been examined. The decline of force was analysed in vitro in mouse soleus and EDL muscles submitted to 60 and 110 Hz continuous stimulation, respectively. Stimulation with this high-frequency fatigue (HFF) protocol, in Ca2+-free conditions, caused in soleus muscle a dramatic increase of fatigue, while in the presence of high Ca2+ fatigue was reduced. In EDL muscle, HFF was not aVected by external Ca2+ levels either way, suggesting that external Ca2+ plays a general protective role only in soleus. Calciseptine, a speciWc antagonist of the cardiac isoform ([afii9825]1C) of the dihydropyri-dine receptor, gadolinium, a blocker of both stretch-activated and store-operated Ca2+ channels, as well as inhibitors of P2X receptors did not aVect the development of HFF. Conversely, the Ca2+ ionophore A23187 increased
the protective action of extracellular Ca2+. KB-R7943, a selective inhibitor of the reverse mode of NCX, produced an eVect similar to that of Ca2+-free solution. These results indicate that a transmembrane Ca2+ inXux, mainly through NCX, may play a protective role during HFF development in soleus muscle.
Keywords Dihydropyridine receptors Stretch-activated Ca2+ channels Store-operated Ca2+ channels P2X receptors Na+/Ca2+ exchanger
Introduction
Muscle contraction is triggered by an increase in concentration of myoplasmic Ca2+ released from sarcoplasmic reticulum (SR). In skeletal muscle Ca2+ release from the SR is dependent on conformational interaction between the activated voltage-gated Ca2+ channel, the dihydropyridine receptor (DHPR), and the SR Ca2+-release channel (Lamb 2000). However, there is some evidence that skeletal muscle contraction can be modulated by extracellular Ca2+. Elevation of extracellular Ca2+ level protects against fatigue produced by brief repeated tetani at low frequency (Cairns et al. 1998).
The aim of the present work was to further investigate the role of extracellular Ca2+ in fatigue development. The study was carried out in high-frequency fatigue (HFF), which is an experimental form of muscle...