Aging and chloride channel regulation in rat fast-twitch muscle fibres

By the use of pharmacological tools, we tested the hypothesis that age-related alterations in the regulatory pathways of chloride channels might contribute to the lowered chloride conductance (GCl) found in skeletal muscle of aged rats. The resting GCl of extensor digitorum longus (EDL) muscles from adult rats either young (3-4 months old) or aged (29 months old) was measured by means of computerized intracellular microelectrode recordings. In EDL muscle from 3 to 4-month-old rats, 4-beta-phorbol 12,13-dibutyrate (4-beta-PDB), a direct activator of protein kinase C (PKC), decreased GCl in a concentration-dependent manner. The same effect was exerted by cholera toxin. The effects of both the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activation of PKC accounts for the decrease of GCl. An increase of cytosolic Ca2+ by the ionophore A23187 also significantly decreased GCl by 25%. In EDL muscles from aged rats, 4-beta-PDB was 20-fold more potent in blocking GCl than in muscles from younger controls, and the ionophore blocked GCl by 40%. On the other hand, cholera toxin was ineffective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of the aging process.