Elevation of Mitochondrial Ca²⁺ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse...

Soleus muscle fibres display modest changes in tetanic force and [Ca²⁺]_i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca²⁺ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus muscles of adult mice. Mitochondrial Ca²⁺ was measured with rhod-2 in intact fibres. Fatigue was induced by 70 Hz, 350 ms tetani given at 2 s intervals in the absence and presence of 10 µM CGP-37157, a potent inhibitor of the mitochondrial Na⁺-Ca²⁺ exchanger. In soleus fibres fatigued in the absence of CGP-37157, tetanic force was significantly reduced by about 30% at the end of the fatiguing stimulation, while mitochondrial [Ca²⁺] increased to a maximum after about 50 tetani and returned to its resting level within 20 min after the end of the stimulation. In the presence of CGP-37157, the maximal mitochondrial [Ca²⁺] increase was more than twice that in control fibres. In addition, fatigue developed more rapidly and force remained depressed after the end of the stimulation. No difference in mitochondrial membrane potential or ROS production was seen between control and CGP-37157 conditions. We conclude that while modest increases in mitochondrial Ca² may be beneficial, excessive mitochondrial Ca² loading depresses muscle function.