Submitted on February 21, 2008
Revised on June 1, 2008
Accepted on June 22, 2008
Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease
Lars Larsson1, Xin Wang2, Fushun Yu1, Peter Höök1, Kristian Borg3, Stephen M. Chong2, and J.-P. Jin2*
1 Uppsala University
2 Northwestern University
3 Karolinska Institutet
* To whom correspondence should be addressed. E-mail: jpjin{at}northwestern.edu.
Slow troponin T (TnT) plays an indispensable role in skeletal muscle function. Alternative RNA splicing in the N-terminal region produces high and low molecular weight (HMW and 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 up-regulated in the demyelination form type 1, but not in the axonal form type 2, CMT muscles. Contractility analysis showed an increased specific force in single fibers isolated from CMT1, but not CMT2, muscles in comparison with that of control muscles. However, in vitro motility assay showed normal velocity of 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 the contractility change, LMW and HMW slow TnT isoforms showed differences in molecular conformation in the conserved central and C-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 up-regulation 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.
