The KATP channel is a molecular sensor of atrophy in skeletal muscle.
The involvement of ATP-sensitive K(+) (K(ATP)) channels in the atrophy of slow-twitch (MHC-I) soleus (SOL) and fast-twitch (MHC-IIa) flexor digitorum brevis (FDB) muscles was investigated in vivo in 14-day-hindlimb-unloaded (14-HU) rats, an animal model of disuse, and in vitro in drug-induced muscle atrophy. Patch-clamp and gene expression experiments were performed in combination with measurements of fibre diameters used as an index of atrophy, and with MHC labelling in 14-HU rats and controls. A down-regulation of K(ATP) channel subunits Kir6.2, SUR1 and SUR2B with marked atrophy and incomplete phenotype transition were observed in SOL of 14-HU rats. The observed changes in K(ATP) currents were well correlated with changes in fibre diameters and SUR1 expression, as well as with MHC-IIa expression. Half of the SOL fibres of 14-HU rats had reduced diameter and K(ATP) currents and were labelled by MHC-I antibodies. Non-atrophic fibres were labelled by MHC-IIa (22%) antibodies and had enhanced K(ATP) currents, or were labelled by MHC-I (28%) antibodies but had normal current. FDB was not affected in 14-HU rats and this is related to the high expression/activity of Kir6.2/SUR1 subunits characterizing this muscle phenotype. The long-term incubation of the control muscles in vitro with the K(ATP) channel blocker glibenclamide (10(6)m) reduced the K(ATP) currents with atrophy and these effects were prevented by the K(ATP) channel opener diazoxide (10(4)m). The in vivo down-regulation of SUR1, and possibly of Kir6.2 and SUR2B, or their in vitro pharmacological blockade activates atrophic signalling in skeletal muscle. All these findings suggest a new role for the K(ATP) channel as a molecular sensor of atrophy.
Tricarico
Domenico
D
Pharmacobiology Department, Faculty of Pharmacy, University of Bari, Via Orabona No. 4, 70120 Bari, Italy. dtricarico@farmbiol.uniba.it
Mele
Antonietta
A
Camerino
Giulia Maria
GM
Bottinelli
Roberto
R
Brocca
Lorenza
L
Frigeri
Antonio
A
Svelto
Maria
M
George
Alfred L
AL
Camerino
Diana Conte
DC
D000818:Animals; D015640:Ion Channel Gating; D054086:KATP Channels / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000503:physiopathology*; D051381:Rats
D054086:KATP Channels