The N-Terminal Fragment of Urine Titin Is Not a Product of Degradation by Calpain 3.

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY Muscle & Nerve Pub Date : 2025-03-01 Epub Date: 2025-01-08 DOI:10.1002/mus.28340

Yoshinori Nambu, Tsuyoshi Matsumura, Kyoka Machida, Rie Tsutsumi, Shoji Hata, Fumiko Shinkai-Ouchi, Yasuko Ono, Kayo Osawa, Taku Shirakawa, Ryosuke Bo, Hisahide Nishio, Hiroshi Sakaue, Hiroyuki Awano, Masafumi Matsuo

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Abstract

Introduction: A 20 kDa fragment at the N-terminus of titin is highly excreted in the urine of patients with Duchenne muscular dystrophy (DMD), making urine titin a prominent biomarker for muscle breakdown. This N-terminal fragment is presumed to be a product of degradation by a protein-degrading enzyme, calpain 3; however, whether calpain 3 is required remains unclear. We aimed to determine whether urine titin elevation occurs in the absence of calpain 3.

Methods: We measured urine titin by ELISA in two genetically confirmed limb-girdle muscular dystrophy type R1(LGMDR1) patients, 11 other LGMD patients, and five healthy controls. Five Capn3-/- and nine wild-type mice were also examined.

Results: Urine titin in LGMDR1 patients was ~100-fold higher than in controls (median 112.3 vs. 1.3 pmol/mg Cr, p < 0.0001), with no difference between LGMDR1 and other LGMD subtypes. Similarly, urine titin levels in Capn3-/- mice were more than four times higher than normal (p < 0.01).

Discussion: These results suggest the involvement of other protein-degrading enzymes leading to the production of the N-terminal fragment.

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尿Titin的n端片段不是钙蛋白酶3降解的产物。

在杜氏肌营养不良（DMD）患者的尿液中，titin的n端有一个20kda的片段大量排出，这使得尿titin成为肌肉分解的重要生物标志物。这个n端片段被认为是蛋白质降解酶钙蛋白酶3降解的产物；然而，是否需要calpain3仍不清楚。我们的目的是确定尿titin升高是否发生在缺乏钙蛋白酶3的情况下。方法：采用ELISA法测定2例经基因证实的R1型肢体肌营养不良（LGMDR1）患者、11例其他LGMD患者和5例健康对照者的尿titin。5只Capn3-/-小鼠和9只野生型小鼠也进行了检测。结果：LGMDR1患者的尿titin比对照组高约100倍（中位数为112.3 vs. 1.3 pmol/mg Cr, p）。讨论：这些结果表明其他蛋白质降解酶参与导致n端片段的产生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Muscle & Nerve 医学-临床神经学

CiteScore

6.40

自引率

5.90%

发文量

287

审稿时长

3-6 weeks

期刊介绍： Muscle & Nerve is an international and interdisciplinary publication of original contributions, in both health and disease, concerning studies of the muscle, the neuromuscular junction, the peripheral motor, sensory and autonomic neurons, and the central nervous system where the behavior of the peripheral nervous system is clarified. Appearing monthly, Muscle & Nerve publishes clinical studies and clinically relevant research reports in the fields of anatomy, biochemistry, cell biology, electrophysiology and electrodiagnosis, epidemiology, genetics, immunology, pathology, pharmacology, physiology, toxicology, and virology. The Journal welcomes articles and reports on basic clinical electrophysiology and electrodiagnosis. We expedite some papers dealing with timely topics to keep up with the fast-moving pace of science, based on the referees'' recommendation.