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

Overview
Journal Muscle Nerve
Date 2025 Jan 8
PMID 39777416
Authors
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
Affiliations
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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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