Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor.
(1) Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. (5) Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.
Pierno
Sabata
S
Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Italy.
De Luca
Annamaria
A
Desaphy
Jean-François
JF
Fraysse
Bodvael
B
Liantonio
Antonella
A
Didonna
Maria Paola
MP
Lograno
Marcello
M
Cocchi
Daniela
D
Smith
Roy G
RG
Camerino
Diana Conte
DC
D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D054439:Ghrelin; D013006:Growth Hormone / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D036361:Peptide Hormones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D054440:Receptors, Ghrelin
D054439:Ghrelin; D009842:Oligopeptides; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C086184:hexarelin; D013006:Growth Hormone