Troponin C, skeletal muscle (TNNC2)

Troponin C, skeletal muscle (specifically the fast-twitch isoform, TNNC2) is a critical calcium-binding protein located within the troponin complex of fast-twitch skeletal muscle fibers (UniProt P02585). It serves as the primary calcium sensor that initiates muscle contraction; upon binding calcium ions released from the sarcoplasmic reticulum, it undergoes a conformational change that moves the tropomyosin-troponin complex to expose myosin-binding sites on actin filaments (PubMed: 22403035). This protein is a major therapeutic target for treating neuromuscular conditions characterized by muscle weakness and fatigue, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) (ClinicalTrials.gov). \n\nPharmacological agents known as fast skeletal muscle troponin activators (FSTAs), such as reldesemtiv, target the troponin complex to increase its sensitivity to calcium. By slowing the dissociation of calcium from troponin C, these drugs enhance muscle contractility and force production at lower levels of neural input, which may improve physical and respiratory function in patients (Hinken et al., 2017). While clinical trials have explored these benefits, challenges remain regarding central nervous system side effects and achieving consistent functional improvements in late-stage trials, as seen in the discontinuation of tirasemtiv and reldesemtiv development for ALS (Cytokinetics, 2023).

Other names

Fast skeletal muscle troponin CTroponin C2TNNC2Troponin C type 2Skeletal muscle troponin C

Fast skeletal muscle troponin activators (FSTAs) bind to the fast skeletal troponin complex and slow the rate of calcium dissociation from troponin C. This sensitizes the sarcomere to calcium, increasing the force of muscle contraction at submaximal levels of calcium release and nerve stimulation (Hinken et al., 2017; Malik et al., 2011).