Age-related nitration/dysfunction of myogenic stem cell activator HGF

Area of Science:

• Muscle stem cell biology
• Molecular mechanisms of aging
• Biochemistry of growth factors

Background:

• Mechanical stress activates myogenic stem cells via hepatocyte growth factor (HGF) and c-met signaling.
• Aging is associated with impaired muscle regeneration and atrophy, a condition known as sarcopenia.

Purpose of the Study:

• To investigate the molecular changes in HGF with aging.
• To determine the impact of these changes on myogenic stem cell activation and muscle homeostasis.

Main Methods:

• Biochemical assays to assess HGF nitration and c-met binding.
• In vivo immunofluorescence microscopy on rat hind limb muscles across different age groups.
• Development and use of specific monoclonal antibodies (mAbs) against nitrated HGF residues (Y198 and Y250).

Main Results:

• Extracellular HGF undergoes tyrosine residue (Y) nitration with aging, specifically at Y198 and Y250 within c-met binding domains.
• Nitrated HGF exhibits reduced binding affinity to its receptor, c-met.
• In vivo studies confirmed age-related increases in nitrated HGF in fast myofibers (IIa and IIx) of rat hind limb muscles.
• HGF nitration was found to be specific among major growth factors studied.

Conclusions:

• HGF nitration with aging inhibits myogenic stem cell dynamics by disrupting HGF-c-met signaling.
• This molecular mechanism contributes to age-related muscle atrophy, impaired regeneration, fibrosis, sarcopenia, and frailty.
• Findings provide a basis for understanding and potentially targeting age-related muscle decline.