A cellular/biochemical study of diabetic myopathy in fast and slow twitch skeletal muscle or rats will be conducted over five years. Insulin dependent diabetes will be induced in WKY rates by injection of streptozotocin. The specific objectives are to (1) quantify the functional capacity of the fast-twitch extensor digitorum longus (ed1) and slow-twitch soleus muscles of both acutely diabetic (4 days after treatment) and long- term diabetic rats (>5 weeks) to generate and maintain tension, and measure the specific energetic costs of contractile activity. The energy cost of contraction will be measured by determining oxygen consumption and lactate evolution after tetanic stimulation, and the time-course of aerobic recovery metabolism will be determined. Maximum twitch and tetanic force will be measured. (2) Determine the nature and extent of changes in the myosin isoenzyme composition of edl and soleus of diabetic rats. Myosin isoenzymes will be analyzed by nondenaturing and SDS gel electrophoresis. (3) Determine the relative capacity of muscle from diabetic rats to maintain intracellular concentrations to controls. In vivo and in vitro experiments will use 3lP-nuclear magnetic resonance to monitor changes in high-energy phosphates during graded consequence of motoneuron atrophy. Diabetic neuropathy will be treated with aldose reductase inhibitors and by dietary supplementation of myo-inositol. Conduction velocity of the sciatic nerve will be measured and correlated with the extent of diabetic myopathy in the soleus and edl of treated rats, as determined by measurements of contractile function. Results of the proposed studies will provide information that could prove useful for designing effective treatments for the prevention of diabetic myopathy in humans. This information also should contribute to our basic understanding of the mechanisms and functional significance of normal adaptation in muscle.
