Consequences of Reduced Troponin-C Calcium Binding Affinity on Slow Skeletal Muscle

Abstract

We recently reported significant alterations of mouse cardiac function caused by a mutation (D73N) in cardiac troponin C (TnC) that results in reduced calcium affinity (McConnell et al., Front. Striated Mus. Physiol., doi.org/10.3389/fphys.2015.00242). Many of the cardiac alterations resemble the pathophysiology associated with dilated cardiomyopathy. The heart and slow fibers in skeletal muscle normally express the same isoform of TnC. We, therefore, tested whether the contractile properties of the soleus muscle in mice with the same TnC mutation are altered. Intact soleus muscles were isolated from wild type (WT) and heterozygous knock-in (D73N) mice and contractile properties were measured. Peak forces during isometric twitches and tetani, normalized with muscle cross-sectional area, did not differ between WT and D73N muscles. The times to peak twitch force and to one-half relaxation during twitches and tetani were significantly shorter in D73N muscles. There was a significantly greater reduction in force, over a two-minute fatigue test, in D73N muscles. The force/pCa relationship was measured in skinned slow fibers from the soleus of WT and D73N mice. The pCa50 of the force/pCa curve was significantly different between WT and D73N slow fibers (mean ± SEM: 6.47 ± 0.04 and 6.02 ± 0.02, respectively).The results demonstrate that a mutation in TnC that leads to dilated cardiomyopathy can also induce profound alterations in skeletal muscle function, potentially exacerbating the morbidity associated with cardiomyopathy.