CMT 1 but not 2: Adaptation by alternative RNA splicing of slow troponin T isofo

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Am J Physiol Cell Physiol. 2008 Jun 25.

Adaptation by alternative RNA splicing of slow troponin T isoforms in

type 1 but not type 2 Charcot-Marie-Tooth disease.

Larsson L, Wang X, Yu F, Höök P, Borg K, Chong SM, Jin JP.

Uppsala University.

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.