Age-related nitration/dysfunction of myogenic stem cell activator HGF |
| |
Authors: | Alaa Elgaabari Nana Imatomi Hirochika Kido Takashi Nakashima Shoko Okuda Yoshitaka Manabe Shoko Sawano Wataru Mizunoya Ryuki Kaneko Sakiho Tanaka Takahiro Maeno Yuji Matsuyoshi Miyumi Seki So Kuwakado Kahona Zushi Nasibeh Daneshvar Mako Nakamura Takahiro Suzuki Kenji Sunagawa Judy E. Anderson Ronald E. Allen Ryuichi Tatsumi |
| |
Affiliation: | 1. Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan;2. Department of Bioscience and Biotechnology, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan;3. Department of Orthopaedic Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan;4. Department of Biological Sciences, Faculty of Science, University of Manitoba, Winnipeg, Manitoba, Canada;5. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyushu University, Fukuoka, Japan;6. The School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA |
| |
Abstract: | Mechanical perturbation triggers activation of resident myogenic stem cells to enter the cell cycle through a cascade of events including hepatocyte growth factor (HGF) release from its extracellular tethering and the subsequent presentation to signaling-receptor c-met. Here, we show that with aging, extracellular HGF undergoes tyrosine-residue (Y) nitration and loses c-met binding, thereby disturbing muscle homeostasis. Biochemical studies demonstrated that nitration/dysfunction is specific to HGF among other major growth factors and is characterized by its locations at Y198 and Y250 in c-met-binding domains. Direct-immunofluorescence microscopy of lower hind limb muscles from three age groups of rat, provided direct in vivo evidence for age-related increases in nitration of ECM-bound HGF, preferentially stained for anti-nitrated Y198 and Y250-HGF mAbs (raised in-house) in fast IIa and IIx myofibers. Overall, findings highlight inhibitory impacts of HGF nitration on myogenic stem cell dynamics, pioneering a cogent discussion for better understanding age-related muscle atrophy and impaired regeneration with fibrosis (including sarcopenia and frailty). |
| |
Keywords: | age-related muscle atrophy fast myofiber fibrosis hepatocyte growth factor (HGF) peroxynitrite regeneration resident myogenic stem cell tyrosine nitration |
|
|