| Autor: |
Kumagai H; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States.; Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan., Kim SJ; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Miller B; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Natsume T; Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.; Faculty of Medicine, Tokai University, Kanagawa, Japan., Wan J; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Kumagai ME; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States.; Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, California, United States., Ramirez R 2nd; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Lee SH; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Sato A; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Mehta HH; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Yen K; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States., Cohen P; The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States. |
| Abstrakt: |
Mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c), a mitochondrial microprotein, has been described as a novel regulator of glucose and lipid metabolism. In addition to its role as a metabolic regulator, MOTS-c prevents skeletal muscle atrophy in high fat-fed mice. Here, we examined the preventive effect of MOTS-c on skeletal muscle mass, using an immobilization-induced muscle atrophy model, and explored its underlying mechanisms. Male C57BL/6J mice (10 wk old) were randomly assigned to one of the three experimental groups: nonimmobilization control group (sterilized water injection), immobilization control group (sterilized water injection), and immobilization and MOTS-c-treated group (15 mg/kg/day MOTS-c injection). We used casting tape for the immobilization experiment. After 8 days of the experimental period, skeletal muscle samples were collected and used for Western blotting, RNA sequencing, and lipid and collagen assays. Immobilization reduced ∼15% of muscle mass, whereas MOTS-c treatment attenuated muscle loss, with only a 5% reduction. MOTS-c treatment also normalized phospho-AKT, phospho-FOXO1, and phospho-FOXO3a expression levels and reduced circulating inflammatory cytokines, such as interleukin-1b (IL-1β), interleukin-6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1), in immobilized mice. Unbiased RNA sequencing and its downstream analyses demonstrated that MOTS-c modified adipogenesis-modulating gene expression within the peroxisome proliferator-activated receptor (PPAR) pathway. Supporting this observation, muscle fatty acid levels were lower in the MOTS-c-treated group than in the casted control mice. These results suggest that MOTS-c treatment inhibits skeletal muscle lipid infiltration by regulating adipogenesis-related genes and prevents immobilization-induced muscle atrophy. NEW & NOTEWORTHY MOTS-c, a mitochondrial microprotein, attenuates immobilization-induced skeletal muscle atrophy. MOTS-c treatment improves systemic inflammation and skeletal muscle AKT/FOXOs signaling pathways. Furthermore, unbiased RNA sequencing and subsequent assays revealed that MOTS-c prevents lipid infiltration in skeletal muscle. Since lipid accumulation is one of the common pathologies among other skeletal muscle atrophies induced by aging, obesity, cancer cachexia, and denervation, MOTS-c treatment could be effective in other muscle atrophy models as well. |
