AGING AND CHLORIDE CHANNEL REGULATION IN RAT FAST-TWITCH MUSCLE-FIBERS

By the use of pharmacological tools, we tested the hypothesis that age -related alterations in the regulatory pathways of chloride channels m ight contribute to the lowered chloride conductance (G(C1)) found in s keletal muscle of aged rats. The resting G(C1) of extensor digitorum l ongus (EDL) muscles from adult rats either young (3-4 months old) or a ged (29 months old) was measured by means of computerized intracellula r 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 p rotein kinase C (PKC), decreased G(C1) in a concentration-dependent ma nner. The same effect was exerted by cholera toxin. The effects of bot h the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activa tion of PKC accounts for the decrease of G(C1). An increase of cytosol ic Ca2+ by the ionophore A23187 also significantly decreased G(C1) by 25%. In EDL muscles from aged rats, 4-beta-PDB was 20-fold more potent in blocking G(C1) than in muscles from younger controls, and the iono phore blocked G(C1) by 40%. On the other hand, cholera toxin was ineff ective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of th e aging process.