Ghrelin Receptor Deletion or Pharmacological Inhibition Improves Muscle Function in Aging Male Mice

Area of Science:

• Gerontology
• Muscle Physiology
• Molecular Biology

Background:

• Sarcopenia, characterized by age-related muscle loss and weakness, is a significant unmet medical need with no approved pharmacological treatments.
• Growth hormone secretagogue receptor (GHSR)-1a activation influences food intake and has anabolic effects, but its role in aging muscle is unclear.

Purpose of the Study:

• To investigate the impact of GHSR-1a deletion on age-related sarcopenia.
• To explore the effects of pharmacological GHSR-1a inhibition on muscle function and metabolism.

Main Methods:

• Comparison of young and aged male GHSR-1a knockout (KO) and wildtype (WT) mice (6, 24, 28 months).
• Assessment of muscle mass, strength, and endurance.
• Analysis of mitochondrial biogenesis (PGC-1α) and mitophagy (PINK1/p62) markers.
• Pharmacological inhibition of GHSR-1a using PF-5190457 in WT mice.

Main Results:

• GHSR-1a deletion improved muscle fatigue resistance, endurance, and strength in aged mice without affecting muscle mass or longevity.
• Mitochondrial biogenesis and mitophagy markers were enhanced in aged KO mice.
• Pharmacological inhibition with PF-5190457 mimicked KO effects on endurance and mitochondrial markers, also reducing body weight and adiposity.

Conclusions:

• GHSR-1a deletion and pharmacological inhibition enhance muscle endurance and mitochondrial function during aging.
• GHSR-1a represents a promising therapeutic target for mitigating age-related sarcopenia.