Troponin T nuclear localization and its role in aging skeletal muscle

Troponin T (TnT) is known to mediate the interaction between Tn complex and tropomyosin (Tm), which is essential for calcium-activated striated muscle contraction. This regulatory function takes place in the myoplasm, where TnT binds Tm. However, recent findings of troponin I and Tm nuclear translocation in Drosophila and mammalian cells imply other roles for the Tn–Tm complex. We hypothesized that TnT plays a nonclassical role through nuclear translocation. Immunoblotting with different antibodies targeting the NH2- or COOH-terminal region uncovered a pool of fast skeletal muscle TnT3 localized in the nuclear fraction of mouse skeletal muscle as either an intact or fragmented protein. Construction of TnT3–DsRed fusion proteins led to the further observation that TnT3 fragments are closely related to nucleolus and RNA polymerase activity, suggesting a role for TnT3 in regulating transcription. Functionally, overexpression of TnT3 fragments produced significant defects in nuclear shape and caused high levels of apoptosis. Interestingly, nuclear TnT3 and its fragments were highly regulated by aging, thus creating a possible link between the deleterious effects of TnT3 and sarcopenia. We propose that changes in nuclear TnT3 and its fragments cause the number of myonuclei to decrease with age, contributing to muscle damage and wasting.