Abstract
Sarcopenia, the decline in muscle mass and functionality during aging, might arise from age-associated endocrine dysfunction. Ghrelin is a hormone circulating in both acylated (AG) and unacylated (UnAG) forms with anti-atrophic activity on skeletal muscle. Here, we show that not only lifelong overexpression of UnAG (Tg) in mice, but also the deletion of ghrelin gene (Ghrl KO) attenuated the age-associated muscle atrophy and functionality decline, as well as systemic inflammation. Yet, the aging of Tg and Ghrl KO mice occurs with different dynamics: while old Tg mice seem to preserve the characteristics of young animals, Ghrl KO mice features deteriorate with aging. However, young Ghrl KO mice show more favorable traits compared to WT animals that result, on the whole, in better performances in aged Ghrl KO animals. Treatment with pharmacological doses of UnAG improved muscle performance in old mice without modifying the feeding behavior, body weight, and adipose tissue mass. The antiatrophic effect on muscle mass did not correlate with modifications of protein catabolism. However, UnAG treatment induced a strong shift towards oxidative metabolism in muscle. Altogether, these data confirmed and expanded some of the previously reported findings and advocate for the design of UnAG analogs to treat sarcopenia.
Highlights
Sarcopenia, the decline in muscle mass and functionality during aging, often results in poor balance, higher risk of falls, fractures, immobilization, loss of independence, and increased morbidity and mortality, representing a major health issue in elder individuals [1,2,3].Muscle wasting follows the general decline in trophic hormones or in their ability of eliciting their standard cellular response (“resistance”) and the establishment of a chronic mild inflammatory status characteristic of aging [4].Ghrelin is a gastric hormone peptide circulating in both acylated (AG) and unacylated (UnAG) forms
Beside the already demonstrated age-related increase of acylated ghrelin (AG) [16], in WT mice, we observed a rise in the circulating levels of UnAG (Figure 1A, 1B), a www.aging-us.com phenomenon that could represent a compensatory mechanism to age-induced ghrelin resistance [17]
To address whether ghrelin levels during aging affect sarcopenia development, we examined young (3-monthold), adult (6-month-old), middle-aged (12-month-old), and old (24-month-old) myosin heavy chain 6 (Myh6)/Ghrl transgenic mice characterized by high levels of circulating UnAG, up to 100 times more than WT animals (Tg; [7, 13]), their WT littermates, and ghrelin knockout (Ghrl KO; [22]) mice, lacking all the gene-derived peptides
Summary
Sarcopenia, the decline in muscle mass and functionality during aging, often results in poor balance, higher risk of falls, fractures, immobilization, loss of independence, and increased morbidity and mortality, representing a major health issue in elder individuals [1,2,3].Muscle wasting follows the general decline in trophic hormones or in their ability of eliciting their standard cellular response (“resistance”) and the establishment of a chronic mild inflammatory status characteristic of aging [4].Ghrelin is a gastric hormone peptide circulating in both acylated (AG) and unacylated (UnAG) forms. UnAG does not induce GH release and has no direct effects on food intake, but it shares with AG several biological activities both in vitro and in vivo independently of the expression of AG receptor In vivo, both AG and UnAG protect Ghsr KO mice from fasting- and denervation-induced skeletal muscle atrophy, proving the existence of a yet unidentified receptor that mediates the common AG and UnAG biological activities [7]. Both AG and UnAG have direct biological activities in vitro on skeletal muscle, including promotion of myoblast differentiation [8], protection from atrophy [7], and stimulation of mitochondrial respiration capacity [9]. UnAG boosts muscle satellite cell activity, activates autophagy and mitophagy, and stimulates insulin sensitivity, promoting muscle regeneration or preventing skeletal mass loss in different disease models, including hindlimb ischemia, high-fat dietinduced diabetes, and chronic kidney disease [10,11,12,13,14]
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