Calcitonin gene-related peptide-1 (CGRP-1) is a potent regulator of glycogen metabolism in rat skeletal muscle

AbstractWe investigated the effects of CGRP on glucose metabolism in intact rat skeletal muscle preparations that are largely composed of either type I (soleus) or II fibres (e.g. extensor digitorum longus (EDL) or epitrochlearis muscles). CGRP-1 inhibited insulin-stimulated glycogen synthesis in both soleus and EDL muscle preparations. Rat CGRP-1 was a potent stimulator of glycogenolysis only in muscles composed of type II fibres, which depend on high rates of glycogenolysis to produce high power outputs. These results may provide the basis for understanding how CGRP regulate glycogenolysis in type II fibres in vivo

Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats

BACKGROUND: Intracellular calcium (Ca(2+)) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy. Treatment with triethylenetetramine (TETA), a divalent-copper-selective chelator, improves cardiac structure and function in patients and rats with diabetic cardiomyopathy, but the molecular basis of this action is uncertain. Here, we used TETA to probe potential linkages between left-ventricular (LV) copper and Ca(2+) homeostasis, and cardiac function and structure in diabetic cardiomyopathy. METHODS: We treated streptozotocin-diabetic rats with a TETA-dosage known to ameliorate LV hypertrophy in patients with diabetic cardiomyopathy. Drug treatment was begun either one (preventative protocol) or eight (restorative protocol) weeks after diabetes induction and continued thereafter for seven or eight weeks, respectively. Total copper content of the LV wall was determined, and simultaneous measurements of intracellular calcium concentrations and isometric contraction were made in LV trabeculae isolated from control, diabetic and TETA-treated diabetic rats. RESULTS: Total myocardial copper levels became deficient in untreated diabetes but were normalized by TETA-treatment. Cardiac contractility was markedly depressed by diabetes but TETA prevented this effect. Neither diabetes nor TETA exerted significant effects on peak or resting [Ca(2+)](i). However, diabetic rats showed extensive cardiac remodelling and decreased myofibrillar calcium sensitivity, consistent with observed increases in phosphorylation of troponin I, whereas these changes were all prevented by TETA. CONCLUSIONS: Diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates myocardial copper deficiency, whereas TETA treatment prevents this response and maintains the integrity of cardiac structure and myofibrillar calcium sensitivity. Altered calcium homeostasis may not be the primary defect in diabetic cardiomyopathy. Rather, a newly-described copper-mediated mechanism may cause this disease