Inhibition of
hepatic glycogen phosphorylase is a promising treatment strategy for attenuating
hyperglycemia in
type 2 diabetes. Crystallographic studies indicate, however, that selectivity between
glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Furthermore,
glycogen phosphorylase activity is critical for normal skeletal muscle function, and thus
fatigue may represent a major development hurdle for this therapeutic strategy. We have carried out the first systematic evaluation of this important issue. The rat gastrocnemius-plantaris-soleus (GPS) muscle was isolated and perfused with a red cell
suspension, containing 3 micromol/l
glycogen phosphorylase inhibitor (GPi) or vehicle (control). After 60 min, the GPS muscle was snap-frozen (rest, n = 11 per group) or underwent 20 s of maximal contraction (n = 8, control; n = 9, GPi) or 10 min of submaximal contraction (n = 10 per group). GPi pretreatment reduced the activation of the
glycogen phosphorylase a form by 16% at rest, 25% after 20 s, and 44% after 10 min of contraction compared with the corresponding control.
AMP-mediated
glycogen phosphorylase activation was impaired only
at 10 min (by 21%). GPi transiently reduced muscle
lactate production during contraction, but other than this, muscle energy metabolism and function remained unaffected at both contraction intensities. These data indicate that
glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity.