Reduced Ghrelin Receptor Activity Improves Mitochondrial Function and Muscle Function in Aged Mice

Key Takeaways

• GHSR-1a knockout boosts muscle endurance in aged mice
• Mitochondrial biogenesis markers PGC‑1α rise with GHSR inhibition
• Inverse agonist PF‑5190457 improves endurance without increasing muscle mass
• PF‑5190457 reduces body weight and adiposity, unlike genetic deletion
• No extension of lifespan observed despite functional gains

Pulse Analysis

Sarcopenia, the progressive loss of muscle strength and mass with age, remains a pressing clinical challenge with no approved pharmacologic remedies. The ghrelin receptor (GHSR‑1a) traditionally stimulates appetite and short‑term anabolic pathways, but its chronic role in aging muscle has been ambiguous. By interrogating both genetic and pharmacologic suppression of GHSR‑1a, researchers aimed to uncover whether dampening this signaling could revitalize mitochondrial health—a key driver of muscle endurance.

In a series of experiments, male mice lacking GHSR‑1a displayed markedly improved fatigue resistance, endurance, and grip strength compared with wild‑type controls, despite unchanged muscle mass. Molecular analyses revealed up‑regulation of the mitochondrial biogenesis co‑activator PGC‑1α and enhanced mitophagy markers such as PINK1, p62, LC3II, and Bnip3. Parallel treatment with the small‑molecule inverse agonist PF‑5190457 reproduced these functional gains and uniquely reduced overall body weight and adiposity, suggesting a broader metabolic impact beyond muscle tissue.

The study positions GHSR‑1a inhibition as a promising avenue for sarcopenia therapeutics, emphasizing functional restoration over hypertrophy. However, the lack of effect on muscle bulk and lifespan tempers expectations, indicating that mitochondrial rejuvenation alone may not reverse all facets of muscle aging. Future research will need to explore combination strategies—perhaps pairing GHSR blockade with agents that promote protein synthesis—to achieve comprehensive benefits for older adults.