Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease

1 Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden; 2 Center for Development and Health Genetics, the Pennsylvania State University, University Park, Pennsylvania; 3 Section of Molecular Cardiology, Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, Illinois; and 4 Division of Rehabilitation Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyds Hospital, Sweden Submitted 21 February 2008 ; accepted in final form 22 June 2008 Slow troponin T (TnT) plays an indispensable role in skeletal muscle function. Alternative RNA splicing in the NH 2 -terminal region produces high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms of slow TnT. Normal adult slow muscle fibers express mainly HMW slow TnT. Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral polyneuropathies caused by various neuronal defects. We found in the present study that LMW slow TnT was significantly upregulated in demyelination form type 1 CMT (CMT1) but not axonal form type 2 CMT (CMT2) muscles. Contractility analysis showed an increased specific force in single fibers isolated from CMT1 but not CMT2 muscles compared with control muscles. However, an in vitro motility assay showed normal velocity of the myosin motor isolated from CMT1 and CMT2 muscle biopsies, consistent with their unchanged myosin isoform contents. Supporting a role of slow TnT isoform regulation in contractility change, LMW and HMW slow TnT isoforms showed differences in the molecular conformation in conserved central and COOH-terminal regions with changed binding affinity for troponin I and tropomyosin. In addition to providing a biochemical marker for the differential diagnosis of CMT, the upregulation of LMW slow TnT isoforms under the distinct pathophysiology of CMT1 demonstrates an adaptation of muscle function to neurological disorders by alternative splicing modification of myofilament proteins. muscle adaptation; demyelination; force and velocity Address for reprint requests and other correspondence: J.-P. Jin, Sect. of Molecular Cardiology, Evanston Northwestern Healthcare, Evanston, IL 60201 (e-mail: jpjin{at}northwestern.edu )