Research Paper Volume 12, Issue 14 pp 13939—13957
Both ghrelin deletion and unacylated ghrelin overexpression preserve muscles in aging mice
- 1 Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- 2 Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- 3 Division of Oncology, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milano, Italy
- 4 Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
- 5 Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
- 6 Department of Public Health, Experimental and Forensic Medicine, Institute of Human Anatomy, University of Pavia, Pavia, Italy
- 7 Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
- 8 Center for Health Technologies (CHT), University of Pavia, Pavia, Italy
- 9 Stem Cell Institute, KU Leuven, Leuven, Belgium
- 10 Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
- 11 Division of Orthopaedics and Traumatology, Hospital “Maggiore della Carità”, Novara, Italy
- 12 Istituto Interuniversitario di Miologia (IIM)
Received: April 3, 2020 Accepted: July 13, 2020 Published: July 26, 2020
https://doi.org/10.18632/aging.103802How to Cite
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.
Abbreviations
AG: acylated ghrelin; β-ATPase: ATP-synthase beta-subunit; BLC: B lymphocyte chemoattractant (CXCL13); BMI: body mass index; BSA: bovine serum albumin; CCL11: C-C motif chemokine ligand 11 (eotaxin-1); CCL1: C-C motif chemokine ligand 1 (I-309); COX4: cytochrome c oxidase subunit 4; CSA: cross-sectional area; CXCL13: C-X-C motif chemokine ligand 13 (BLC); DAPI: 4′,6-diamidino-2-phenylindole; EDL: extensor digitorum longus; Fbxo32: F-Box Protein 32 (Atrogin-1); GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GAS: gastrocnemius; GH: growth hormone; Ghrl: ghrelin (gene); Ghsr: growth hormone secretagogue receptor (gene); GHSR-1a: growth hormone secretagogue receptor type 1a; IL-13: interleukin-13; IL-12: interleukin-12; IL-12p70: interleukin-12 70 kDa light chain; KO: knock-out; M-CSF: macrophage colony-stimulating factor; Myh6: myosin heavy chain 6 (gene); PGC1α: PPARγ-coactivator-1-alpha; PBS: Phosphate Buffered Saline; PFA: paraformaldehyde; PPARγ: peroxisome proliferator-activated receptor gamma; Ppif: peptidyl-prolyl cis-trans isomerase, mitochondrial; QUAD: quadriceps; SDF1α: stromal cell-derived factor-1-alpha; SDH: succinate dehydrogenase; SDHA: succinate dehydrogenase complex flavoprotein subunit A; SOL: soleus; TA: tibialis anterior; TFAM: mitochondrial transcription factor A; TNFα: tumor necrosis factor alpha; TNF-R1: tumor necrosis factor receptor 1; Tg: transgenic; UCP1: Uncoupling Protein 1; UnAG: unacylated ghrelin; WT: wild type.