S. Kapur et al., EXPRESSION OF NITRIC-OXIDE SYNTHASE IN SKELETAL-MUSCLE - A NOVEL ROLEFOR NITRIC-OXIDE AS A MODULATOR OF INSULIN ACTION, Diabetes, 46(11), 1997, pp. 1691-1700
Previous studies have shown that nitric oxide synthase (NOS), the enzy
me that catalyzes the formation of nitric oxide (NO), is expressed in
skeletal muscle, The aim of the present study was to test the hypothes
is that NO can modulate glucose metabolism in slow-and fast-twitch ske
letal muscles, Calcium-dependent NOS was detected in skeletal muscle,
and the enzyme activity was greater in fast-type extensor digitorum lo
ngus (EDL) muscles than in slow-type soleus muscles, Both the neuronal
-type (nNOS) and endothelial-type (eNOS) enzymes are expressed in rest
ing skeletal muscles, However, nNOS protein was only detected in EDL m
uscles, whereas eNOS protein contents were comparable in soleus and ED
L muscles, NOS expression in muscle cryosections (diaphorase histochem
istry) was located in vascular endothelium and in muscle fibers, and t
he staining was greater in type IIb than in type I and IIa fibers, The
macrophage-type inducible NOS (iNOS) was not detected in resting musc
le, but endotoxin treatment induced its expression, concomitant with e
levated NO production, iNOS induction was associated with impaired ins
ulin-stimulated glucose uptake in isolated rat muscles, In vitro, NOS
blockade with specific inhibitors did not affect basal or insulin-stim
ulated glucose transport in EDL or soleus muscles, In contrast, the NO
donors GEA 5024 and sodium nitroprusside induced dose-dependent inhib
ition (up to 50%) of maximal insulin-stimulated glucose transport in b
oth muscles with minor effects on basal uptake values, GEA 5024 also b
lunted insulin-stimulated glucose transport and amino acid uptake in c
ultured L6 muscle cells without affecting insulin binding to its recep
tor, On the other hand, the permeable cGMP analogue dibutyryl cGMP did
not affect muscle glucose transport, These results strongly suggest t
hat NO modulates insulin action in both slow-and fast-type skeletal mu
scles, This novel autocrine action of NO in muscle appears to be media
ted by cGMP-independent pathways.