EFFECTS OF CHRONIC GROWTH-HORMONE TREATMENT IN AGED RATS ON THE BIOPHYSICAL AND PHARMACOLOGICAL PROPERTIES OF SKELETAL-MUSCLE CHLORIDE CHANNELS

1 The effects of a 4-month daily treatment with recombinant human grow th hormone (GH) (150 mu g kg(-1)) to aged rats were evaluated on the p assive and active membrane electrical properties of extensor digitorum longus (EDL) muscle fibres in vitro by means of a two intracellular m icroelectrode technique. 2 Chronic GH treatment completely restored th e diameter and the membrane capacitance of aged EDL muscle fibres and significantly lowered the membrane resistance towards the adult value. There was also an increase of the threshold current, a shortening of the latency and an increase of the amplitude of the action potential a nd a significant amelioration of the membrane firing capability. 3 The effects were almost fully attributable to a significant 50% increase of resting conductance to chloride ions (G(Cl)), although an observed restoration of potassium conductance and a possible effect on voltage- activated sodium channels could contribute to the effects. 4 EDL muscl e fibres of untreated aged rats showed a different pharmacological res ponse to 2-(p-chlorophenoxy) propionic acid (CPP) enantiomers from tha t seen in adult rats; the S-(-) isomer was less potent in blocking G(C l) and the R-(+) isomer always increased G(Cl) instead of producing th e typical biphasic effect observed in adult fibres (an increase of G(C l) at 1-10 mu M and a decrease at higher concentrations). The 4-month- GH-treated aged rats showed a pharmacological sensitivity to CPP enant iomers similar to that of adults. 5 The in vitro application of insuli n-like growth factor I (IGF-I), the peripheral mediator of GH, produce d a significant and irreversible increase of G(Cl) of EDL muscle of un treated aged rats, an effect not observed in adults. This effect was c ompletely inhibited by preincubation with 0.5 mu M okadaic acid, sugge sting that the IGF-I receptor transduction pathway can act on the phos phorylation state of the chloride channel through a serine-threonine p rotein phosphatase. 6 The results show that the skeletal muscle chlori de channel is a target of the impairment of GH/IGF-I axis occurring in aged subjects. The acute and chronic effects observed on G(Cl) of age d muscle fibres suggest that the GH/IGF-I stimuli act through a modula tion of channel phosphorylation state and through the synthesis of 'ad ult'-like type chloride channels.