The effects of muscle calcium sensitizer (ck7357) on exercise performance in male Sprague-Dawley rats
Skeletal muscle fatigue has a complex multifaceted etiology in which the ability to regulate intracellular calcium concentration ([Ca2+]i) and the myofibrillar response to elevated [Ca2+]i are key components. Pertinent to this issue, a drug developed by Cytokinetics, Inc. (CK7357), has been shown to increase contractile function via altered myofibrillar Ca2+ sensitivity in in-vitro preparations. We tested the hypothesis that CK7357 would increase the endurance capacity and V.O2peak in young male Sprague-Dawley rats above saline control values. The exercise tolerance test consisted of a progressive exercise test in which each rat initially ran at a speed of 25 m/min up a 10% grade for 15 min. Thereafter the treadmill speed was increased by 5m/min every 15 min until fatigue (i.e., the rat could no longer maintain pace with the treadmill). V.O2peak was determined according to previously established methods used in our laboratory. Each rat initially ran at 25 m/min up a 10% grade for 2-3 minutes. The speed of the treadmill was the increased progressively in a ramp-like manner until fatigue. V.O2peak was defined either as the point at which O2 did not further increase despite increases in treadmill speed or the highest V.O2peak prior to fatigue. CK7357 or saline were administered via gastric gavage. There was a significant increase (P<0.05) in endurance capacity with 10 mg/kg of CK7357, but not at lower (0.5-5 mg/kg) or higher (20-40mg/kg) doses. This improvement in endurance capacity occurred in the absence of any changes in V.O2peak. The highest dose (40 mg/kg) produced a significant decrease (P<0.05) in the endurance capacity as well as V.O2peak. These data demonstrate, for the first time, that the in-vitro observations of increased [Ca2+]i sensitivity and improved muscle function with CK7357 translate to improved whole body exercise performance when gavaged at a dose of 10 mg/kg. Further studies need to be conducted to explore the efficacy of CK7357 in animal models of chronic disease (i.e. CHF and diabetes). It is possible that CK7357 may be a potential ergogenic aid for patients whom enhanced physical capacity could be of significant therapeutic value, and lead to increases in activities of daily living and quality of life.
School:Kansas State University
School Location:USA - Kansas
Source Type:Master's Thesis
Keywords:calcium sensitivity muscle fatigue exercise performance biology animal physiology 0433 health sciences education 0350 general 0566
Date of Publication:01/01/2009