In vitro immuno‐prevention of nitration/dysfunction of myogenic stem cell activator HGF, towards developing a strategy for age‐related muscle atrophy

In response to peroxynitrite (ONOO−) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c‐met, thereby disturbing muscle h...

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Published in:	Aging cell Vol. 23; no. 10; pp. e14337 - n/a
Main Authors:	Tanaka, Sakiho, Elgaabari, Alaa, Seki, Miyumi, Kuwakado, So, Zushi, Kahona, Miyamoto, Junri, Sawano, Shoko, Mizunoya, Wataru, Ehara, Kenshiro, Watanabe, Naruha, Ogawa, Yohei, Imakyure, Hikaru, Fujimaru, Reina, Osaki, Rika, Shitamitsu, Kazuki, Mizoguchi, Kaoru, Ushijima, Tomoki, Maeno, Takahiro, Nakashima, Takashi, Suzuki, Takahiro, Nakamura, Mako, Anderson, Judy E., Tatsumi, Ryuichi
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01-10-2024 John Wiley and Sons Inc
Subjects:	Aging Animals Antigens Atrophy c-Met protein Cell activation Cell culture c‐met binding Fab Fibrosis Hepatocyte growth factor hepatocyte growth factor (HGF) Hepatocyte Growth Factor - metabolism Homeostasis Humans Localization Mice Monoclonal antibodies monoclonal antibody muscle atrophy Muscular Atrophy - metabolism Nitration Peroxynitrite Peroxynitrous Acid - metabolism Peroxynitrous Acid - pharmacology Prevention rat Rats resident myogenic stem satellite cell Sarcopenia Satellite cells Satellite Cells, Skeletal Muscle - metabolism Short Communication Stem cells tyrosine nitration Western blotting peroxynitrite c‐met binding rat hepatocyte growth factor (HGF) muscle atrophy monoclonal antibody resident myogenic stem satellite cell tyrosine nitration
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Summary:	In response to peroxynitrite (ONOO−) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c‐met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti‐HGF monoclonal antibody (mAb) 1H41C10, which was raised in‐house against a synthetic peptide FTSNPEVRnitroY198EV, a site well‐conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non‐nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10‐bound HGF resists peroxynitrite‐induced nitration of Y198. A companion mAb‐1H42F4 presented similar immuno‐reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10‐HGF also withstood Y250 nitration to retain c‐met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10‐Fab confers Y250‐nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration‐dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age‐related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs. Previously, we demonstrated age‐related nitration of ECM‐bound HGF (myogenic stem satellite cell activator), preferentially in fast IIa and IIx myofibers. Rat anti‐HGF monoclonal antibody 1C10 was generated; 1C10‐bound HGF resists peroxynitrite‐induced nitration of HGF‐Y198/Y250 to retain its c‐met binding and satellite cell activation activities in vitro. 1C10‐Fab region confers nitration dysfunction resistance to HGF. This discovery potentially pioneers cogent strategies for counteracting or treating age‐related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1474-9718 1474-9726 1474-9726
DOI:	10.1111/acel.14337