Targeting an Appetite Hormone Receptor for Stronger Muscles

In Aging Cell, researchers have described how suppressing the ghrelin receptor improves muscle function and fights sarcopenia in older mice.

An appetite hormone with negative effects

Ghrelin has been well-documented as stimulating both appetite and growth [1]. However, this hormone, which increases with aging [2], has negative effects in older organisms; deleting ghrelin has been found to restore mitochondrial function, fight obesity, and restore muscle strength in older mice [3], thus delaying the age-related loss of muscle known as sarcopenia.

Removing ghrelin itself, however, may be difficult to translate to the clinic. These researchers, therefore, have chosen to target its receptor instead, noting that targeting its only known receptor “represents a viable anti-sarcopenia strategy” and “may be a more translatable approach than deleting the ghrelin ligand itself.” Therefore, this paper focuses on what happens when GHSR-1a is inhibited through various means in mice.

Less fatigue and more efficient mitochondria

For their first experiment, the researchers created a strain of mice that do not expres GHSR-1a and tested them at 6, 24, and 28 months of age. At 6 months, the mice with GHSR-1a knocked out were smaller than the other mice, in both total weight and lean body mass. However, the GHSR-1a knockout mice were stronger for their weight, and they were strictly stronger at 24 months of age. At 24 months of age, the knockout mice could run nearly 30% longer than wild-type mice, and at 28 months, this number increased to nearly 45%. Overall, metrics of sarcopenia were reduced in the knockout mice with aging.

There were also changes to fiber types, although there were no effects on fiber size. In wild-type mice, the number of IIB muscle fibers gradually declines. In the knockout mice, there was an increase in IIB fibers between 6 and 24 months, although there was a steep decrease between 24 and 28 months.

A direct muscle fatigue test, in which muscles are electrically stimulated in living mice, found that the knockout mice had less fatigue. 6-month-old knockout mice were able to exert more force than wild-type mice of the same age after two minutes or more of stimulation; 28-month-old knockout mice showed advantages over their wild-type counterparts at 30 and 60 seconds.

As expected, these physiological advantages were accompanied by mitochondrial benefits. The knockout mice did not exhibit a significant age-related decrease in citrase synthase the way wild-type mice did, nor did they have significant decreases in mitochondrial DNA (mtDNA) production. PGC-1α, which signals the formation of new mitochondria, increased at 28 months in the knockout mice instead of decreasing, and at that age, the knockout mice also benefited from higher levels of mitophagy, a process that clears out damaged mitochondria.

Reduces sarcopenia but does not improve lifespan

A gene expression analysis confirmed this knockout’s effects against sarcopenia, as the wild-type animals expressed genes in more ways that were associated with this disease. Many of these genes were directly related to mitochondrial respiration, and others were closely connected to muscular performance.

Unfortunately, there were no direct benefits for lifespan; the knockout mice and the wild-type mice lived for approximately the same amount of time.

The researchers then sought to see if these effects could be pharmacologically replicated. They tested PF-5190457, an inhibitor of GHSR-1a, for a month in 9- to 11-month-old mice. As expected, the appetite reduction caused by this inhibition reduced the treated mice’s body weight and fat mass. They also had increases in running time and mitophagy. Similar results were found in 25- to 27-month-old mice.

Targeting the ghrelin receptor is obviously not a cure-all for sarcopenia, as these effects were significant but not perfect. Furthermore, these researchers did not observe the lifespan increases that occurred in mice that had ghrelin targeted more directly [4]. However, this study makes it clear that it may be possible to, counterintuitively, reduce frailty in older organisms by suppressing instead of bolstering a growth hormone receptor.

Literature

[1] Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., & Kangawa, K. (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402(6762), 656-660.

[2] Sun, Y., Garcia, J. M., & Smith, R. G. (2007). Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology, 148(3), 1323-1329.

[3] Guillory, B., Chen, J. A., Patel, S., Luo, J., Splenser, A., Mody, A., … & Garcia, J. M. (2017). Deletion of ghrelin prevents aging‐associated obesity and muscle dysfunction without affecting longevity. Aging Cell, 16(4), 859-869.

[4] Aguiar-Oliveira, M. H., & Bartke, A. (2019). Growth hormone deficiency: health and longevity. Endocrine reviews, 40(2), 575-601.