Upregulation of Unacetylated Ghrelin Slows Age-Related Muscle Loss in Mice

Ghrelin is best known for its role in the mechanisms of hunger, but it has two different forms, only one of which induces hunger. Both forms are known to affect muscle tissue metabolism, and this may be one of the ways in which calorie restriction slows the onset of muscle loss with age, a condition known as sarcopenia. Researchers here increase levels of the non-hunger-inducing ghrelin in mice and show that this does indeed slow the onset and progression of sarcopenia, and thus might be a basis for therapy.

Sarcopenia, the decline in muscle mass and functionality during aging, might arise from age-associated endocrine dysfunction. Indeed, muscle wasting follows the general decline in trophic hormones and the establishment of a chronic mild inflammatory status characteristic of aging. Ghrelin is a gastric hormone peptide circulating in both acylated (AG) and unacylated (UnAG) forms that have anti-atrophic activity on skeletal muscle. AG is the endogenous ligand of the growth hormone secretagogue receptor (GHSR-1a), and it is involved in metabolic regulation and energetic balance through induction of appetite, food intake, and adiposity. UnAG does not induce GH release and has no direct effects on food intake, but it shares with AG several biological activities on cell types lacking AG receptor.

In particular, both AG and UnAG have direct biological activities on skeletal muscle, including promotion of myoblast differentiation and protection from atrophy, in all likelihood by activating a common receptor. Also, UnAG promotes muscle regeneration, stimulation of muscle satellite cell activity, and activates autophagy and mitophagy at higher extent than AG. Age-dependent hypoghrelinemia could participate in the establishment of sarcopenia by facilitating the progression of muscle atrophy and limiting skeletal muscle regeneration capability.

Here, we show that both the deletion of the ghrelin gene (Ghrl KO) and the lifelong overexpression of UnAG (Tg) in mice attenuated the age-associated decline in muscle mass and functionality, seen as larger myofiber areas, lower levels of Atrogin-1, and increased mitochondrial functionality compared to old wild type (WT) animals. Also, both Ghrl KO and Tg animals displayed reduced systemic inflammation and maintenance of brown adipose tissue functionality. While old Tg mice apparently preserved the characteristics of young animals, Ghrl KO mice features deteriorate with aging. However, young Ghrl KO mice show more favorable features compared to WT animals that result, on the whole, in better performances in aged Ghrl KO mice. Altogether, the data collected suggest that, in Ghrl KO mice, it is the lack of AG that is the major determinant factor of their overall better conditions and advocate for the design of analogs to UnAG rather than AG to therapeutically treat sarcopenia in humans.

Link: https://www.eurekalert.org/pub_releases/2020-09/esoe-gmb090320.php

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