Influence of activation frequency on cellular signalling pathways during fatiguing contractions in rat skeletal muscle.

Activation frequency as a regulator of physiological responses in skeletal muscle, independent of contractile force, has received little attention. Here, the length-tension and force-frequency relationships were employed to keep active contractile force equal, despite a twofold difference in stimulation frequency (15 versus 30 Hz). Rat tibialis anterior muscles were tested in situ using 15 Hz stimulation at optimal length (15 Hz) and 30 Hz stimulation at shortened and lengthened positions (30 Hz(sub) and 30 Hz(supra)). Muscles were subjected to 1, 15, 30 and 80 Hz stimulation trains before and after 2 min of fatiguing stimulation. The principal findings were that the two 30 Hz protocols produced greater 38 kDa MAPK (p38) phosphorylation than the 15 Hz protocol (1.4- to 1.5-fold versus 1.1-fold), as well as greater fatigue (65-78 versus 43% decline in contraction force). In contrast, c-jun amino terminal kinase (JNK) phosphorylation appeared most responsive to total (active plus passive) tension such that the changes followed the pattern: 30 Hz(supra) > 15 Hz > 30 Hz(sub), while 44 and 42 kDa extracellular regulated kinase (ERK1/2) phosphorylation was not significantly increased in response to any of the protocols studied. Neither glycogen depletion nor myofibre damage accounted for any of the findings, but a decline in muscle excitation (m-wave) may have contributed to the greater fatigue seen at higher frequencies. These data suggest that neuromuscular activation frequency can influence certain signalling pathways in skeletal muscle, independent of force production.