Lower force and impaired performance during high-intensity electrical stimulation in skeletal muscle of GAMT-deficient knockout mice

1 Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen; 2 Faculty of Human Movement Sciences, Vrije University, Amsterdam; 3 Center for Molecular Neurobiology, University of Hamburg, Hamburg, Germany; 4 Institute for Fundamental and Clinical Human Movement Sciences, Amsterdam, The Netherlands; and 5 Institute for Biophysical and Clinical Research into Human Movement, Manchester Metropolitan University, Cheshire, United Kingdom Submitted 1 February 2005 ; accepted in final form 1 March 2005 Force characteristics of skeletal muscle of knockout mice lacking creatine (Cr) due to a deletion of guanidinoacetate methyltransferase (GAMT) were studied in situ. Medial gastrocnemius muscles of anesthetized GAMT-deficient (GAMT –/– ) and control (Con) littermates were stimulated at optimum length via the sciatic nerve at different stimulation frequencies (60–250 Hz). GAMT –/– mice showed reduced maximal tetanic and twitch force, reduced relative force at 60 Hz, and increased relaxation times. High-intensity fatigue protocols consisting of 30 successive isometric or dynamic contractions showed a strong reduction in force at the beginning of the series in GAMT –/– mice, followed by a smaller reduction compared with Con littermates toward the end of the series. Cr supplementation for 2 days in GAMT –/– animals (GAMT ) resulted in normalization to Con values for relaxation times, relative force at lower stimulation frequencies, and relative force during 30 isometric contractions. Force per muscle mass, however, remained decreased. Furthermore,GAMT mice showed differences compared with both Con and unsupplemented animals in maximal rates of force rise and relaxation times during the isometric protocol as well as in force during the dynamic protocol. Our results show that the absence of Cr plays a direct role in relaxation times, maximal rate of force rise, and force production during high-intensity fatigue protocols. The lower force per muscle mass, however, is probably caused by other factors; i.e., high intracellular guanidinoacetate concentrations. energy metabolism; creatine; fatigue; force characteristics Address for reprint requests and other correspondence: H. E. Kan, Dept. of Radiology (430), Radboud Univ. Nijmegen Medical Center, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands (e-mail: h.kan{at}rad.umcn.nl )