Regulator of Calcineurin1 isoform 4 (RCAN1-4)is an oxidative responsive endogenous intracellular phosphatase that inhibits Calcineurin (Cn). Cnis a ubiquitously expressed serine/threonine protein phosphatase under the control of calcium/calmodulin which has been identified in skeletal muscles. However, so far, RCAN1 expression has never been studied under acute exercise. Experiment: 24 Wistar ratswere grouped in three and were subjected to the same physical exercise protocoland then sacrificed either immediately, or 3 hours or 6 hours after exercise. A control group of 8 rats were sacrificed in the same condition. Three different skeletal muscles were collected: Soleus, a predominantly slow twitch muscle rich in type 1 fibers; Extensor DigitorumLongus (EDL), a fast twitch muscle rich in type 2 fibers; andGastrocnemius a ‘mixed muscle’ which contains both type 1 and type 2 fibers. Results: RCAN1-4 was expressed differently in the three muscles. The content of RCAN1-4 was highest in Soleus and remains unchanged after exercise, However RCAN1-4 increased significantly after exercise until 6 hours in EDL and Gastrocnemius. Expression of Cn decreased in all muscles after exercise. PGC-1? as a marker for mitochondrial biogenesis was assayed, although its expression does not significantly changes in any muscle, but it is more expressed in Soleus. Insight in protein and lipid peroxidation showsdifferent patterns of peroxidation of biomolecule in different muscles. Generally malondialdehydeaugments in all muscles after the exercise; however the level of protein carbonyl content increasedonly in EDL and Gastrocnemius but not in Soleus. Conclusion: Acute exercise up-regulated RCAN1-4 expression in rat EDL and Gastrocnemius. Exhaustive exercise is known to induce oxidative stressand RCAN1-4 induction has been shown to help protect against oxidative stress in other tissues. We propose that RCAN1-4 expression represents an important component of the physiological adaptation to exercise and presently we are conducting more investigation using Diabetes Mellitus and Alzheimer’s disease models.