Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin‐specific receptor

Abstract

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 [DLys-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.

Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles

“…In addition to the smooth muscle, previous studies showed that ghrelin also decrease contractility of cardiac (Bedendi et al, 2003;Soares et al, 2006) and skeletal muscles (Pierno et al, 2003). In the myocardium, PGI 2 release from endocardial endothelial cells was proposed to mediate the inotropic and lusitropic effects of ghrelin (Bedendi et al, 2003;Soares et al, 2006).…”

“…In the skeletal muscle, ghrelin reduces membrane potential, apparently by increasing chloride's permeability. This action is directly dependent of GHSR-1a and is blocked by the specific inhibitor DLys 3 GHRP6 (Pierno et al, 2003). In human vascular smooth muscle, ghrelin appears as the most potent endothelium-independent vasodilator, reversing effectively endothelin-1 (ET-1) mediated constrictions with potency similar to that of adrenomodullin (Wiley and Davenport, 2002).…”

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

“…In particular, pathophysiological conditions of skeletal muscle with a reduced value of gCl, such as aging, drug-induced myopathies, and, again, muscular dystrophy, are characterized by elevated [Ca 2ϩ ] i (11,21,22,31,44), while the increase of gCl, occur-ring in slow-twitch muscle during HU, parallels a decrease of both [Ca 2ϩ ] i and PKC signaling (30,56,57). The pathway for activation of the calcium-dependent PKC occurs via a G protein (20); few endogenous ligands can activate the receptormediated PLC/PKC signaling pathways able to modulate gCl, further supporting the key role of the latter for muscle physiology (55,58,72). For instance, ATP-mediated activation of P2Y1 purinergic receptor acutely modulates gCl, likely for adapting muscle performance during exercise and fatigue (23,72).…”

An olive oil-derived antioxidant mixture ameliorates the age-related decline of skeletal muscle function

“…Our previous findings have demonstrated an important modification of skeletal muscle protein function during aging (Desaphy et al 1998;Pierno et al 2003) and that these modifications can be associated with increased ROS levels. During aging, we found a downregulation of the expression of ClC-1, the skeletal muscle chloride channel which is correlated with an abnormal decrease of the resting chloride conductance (g Cl ; Pierno et al 1999Pierno et al , 2009).…”