Reduced Ghrelin Receptor Activity Improves Mitochondrial Function and Muscle Function in Aged Mice
Researchers here report a novel approach to improving mitochondrial function in aged muscle tissue, involving a reduction in the activity of the ghrelin receptor, either via gene knockout or by using an inverse agonist small molecule. It is interesting to note that while this improves muscle function, it fails to improve either muscle mass or longevity in the treated mice. One might expect to see enhanced mitochondrial function produce at least some effect on those parameters, but the data is the data.
Sarcopenia is characterized by age-related declines in muscle strength and mass, along with impaired physical function. It remains an unmet medical need, and there are no pharmacological interventions approved for this indication. The activation of growth hormone secretagogue receptor (GHSR)-1a, also known as ghrelin receptor, stimulates food intake and has acute anabolic effects. However, its impact on aging muscles remains uncertain. We examined the effects of GHSR-1a deletion on sarcopenia measurements (muscle mass, strength, and endurance) by comparing young and aged male GHSR-1a knockout (KO) and wildtype (WT) mice (6-, 24-, and 28-month-old).
Deletion of GHSR-1a improved muscle fatigue resistance, endurance, and muscle strength during aging without affecting muscle mass or longevity. Since muscle endurance is closely related to mitochondrial function, we examined mitochondrial biogenesis marker PGC-1α and mitophagy signaling via PINK1/p62 and found them improved in old mice with GHSR deletion. Proteomics analysis also revealed that mitochondrial components remain central for maintaining muscle mass and function.
We further investigated the effects of pharmacological inhibition of GHSR-1a by its inverse agonist, PF-5190457, in male WT mice. PF-5190457 mimicked the effects of GHSR-1a deletion, including improved endurance and increased markers of mitochondrial biogenesis (PGC-1α) and different mitophagy markers (LC3II and Bnip3). PF-5190457 also reduced body weight and adiposity, which were not observed with GHSR-1a deletion.