Carbonic Anhydrase III Contributes to Fatigue Tolerance and Recovery of Skeletal Muscle

Abstract

Carbonic anhydrase III (CA3) is a metabolic enzyme with a potential role in regulating intracellular pH. CA3 is highly expressed in slow twitch skeletal muscles. Here we demonstrated that mouse tibialis anterior (TA), a fast twitch muscle, also expresses a high level of CA3 while its myofilament protein contents were similar to that of CA3-negative extensor digitorum longus (EDL) muscle. To investigate the function of CA3 in muscle contractility and tolerance to fatigue, we studied skeletal muscles of CA3 knockout (Car3-/-) mice. Sciatic nerve stimulation-generated in situ contractility of EDL and TA muscles were examined in comparison with wild type controls. The results of isometric twitch and tetanic contractions showed no significant difference between TA and EDL muscle of wild type mice or between Car3-/- and wild type TA muscles. Nonetheless, intermittent fatigue treatment revealed faster fatigue and slower recovery of wild type TA muscle than that of wild type EDL muscle. Car3-/- TA muscle exhibited slower and less fatigue but also slower recovery than that of wild type TA muscle, whereas the ultimate level of force recovery was unchanged. It is suggested that CA3 increases the sensitivity of muscle to fatigue, which might serve as an acute physiological protection. In the meantime, Western-blot detected a low molecular weight fast troponin T (TnT) variant specifically in TA muscle of adult Car3-/- mice, suggesting a chronically adaptive response through alternative RNA splicing. The role of CA3 in fatigue tolerance and recovery of skeletal muscle suggests a molecular therapeutic target for functional enhancement.