Omega‐3 multiple effects increasing glucocorticoid‐induced muscle atrophy: autophagic, AMPK and UPS mechanisms

• Published in: Physiological reports 2019-01, Vol.7 (1), p.e13966-n/a
• Main Authors: Fappi, Alan, Neves, Juliana de C., Kawasaki, Karine A., Bacelar, Luana, Sanches, Leandro N., P. da Silva, Felipe, Larina‐Neto, Rubens, Chadi, Gerson, Zanoteli, Edmar
• Format: Article
• Language: English
• Subjects: Acid phosphatase; Animals; Atrophy; Autophagy; Dexamethasone - adverse effects; Dual energy X-ray absorptiometry; eicosapentaenoic acid; Fatty Acids, Omega-3 - adverse effects; Fatty Acids, Omega-3 - pharmacology; Forkhead Box Protein O3 - metabolism; FOXO3 protein; Gene expression; glucocorticoid; Glucocorticoids; Glucocorticoids - adverse effects; IGF‐1 pathway; Insulin-like growth factors; Male; MEK/ERK pathway; mRNA; muscle atrophy; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Conditions, Disorders and Treatments; Myostatin; Myostatin/Smad2/3 pathway; omega‐3 fatty acid; Original Research; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Physiology; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Kinases - metabolism; Rats; Rats, Wistar; Signalling Pathways; Skeletal Muscle; Smad Proteins - metabolism; Smad2 protein; Ubiquitin; Ubiquitins - metabolism
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13966

Muscle atrophy occurs in many conditions, including use of glucocorticoids. N‐3 (omega‐3) is widely consumed due its healthy properties; however, concomitant use with glucocorticoids can increase its side effects. We evaluated the influences of N‐3 on glucocorticoid atrophy considering IGF‐1, Myostatin, MEK/ERK, AMPK pathways besides the ubiquitin‐proteasome system (UPS) and autophagic/lysosomal systems. Sixty animals constituted six groups: CT, N‐3 (EPA 100 mg/kg/day for 40 days), DEXA 1.25 (DEXA 1.25 mg/kg/day for 10 days), DEXA 1.25 + N3 (EPA for 40 days + DEXA 1.25 mg/kg/day for the last 10 days), DEXA 2.5 (DEXA 2.5 mg/kg/day for 10 days), and DEXA 2.5 + N3 (EPA for 40 days + DEXA 2.5 mg/kg/day for 10 days). Results: N‐3 associated with DEXA increases atrophy (fibers 1 and 2A), FOXO3a, P‐SMAD2/3, Atrogin‐1/MAFbx (mRNA) expression, and autophagic protein markers (LC3II, LC3II/LC3I, LAMP‐1 and acid phosphatase). Additionally, N‐3 supplementation alone decreased P‐FOXO3a, PGC1‐alpha, and type 1 muscle fiber area. Conclusion: N‐3 supplementation increases muscle atrophy caused by DEXA in an autophagic, AMPK and UPS process. Besides the healthy proprieties of omega‐3 (N‐3) to human body its association with pathological conditions or with drugs can shift the cell physiological responses enhancing degradation systems (e.g. autophagic process) or signalizing, processes, in a way not fully elucidated. Trying to better elucidate the increase of dexamethasone (DX) muscle atrophy by N‐3 we assessed different muscle trophic pathways and degradation systems in rats receiving two dosages of DX in association with previous and concomitant EPA/DHA supplementation for 10 days. N‐3 association with DX significantly increases muscle atrophy together with autophagy and Atrogin‐1/REDD‐1 mRNA expressions. N‐3 can potentiate glucocorticoid action in the skeletal muscle acting in different mechanisms.