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

Abstract

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.

Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

“…A recent study [139] demonstrated that omega-3 fatty acids are capable of increasing the activity of the ubiquitin-proteasome system (UPS). UPS is a protein network responsible for inducing muscle atrophy and, if not inhibited, promotes protein breakdown.…”

Effect of dietary fish oil intake on ubiquitin ligase expression during muscle atrophy induced by sciatic nerve denervation in mice

“…For example, Kamolrat and Gray () showed that EPA has an efficacy in augmenting leucine stimulated protein synthesis and reducing protein breakdown in murine C2C12 myotubes. Similarly, Fappi et al () found that 30‐days of n‐3 PUFA supplementation (100 mg kg −1 day −1 of EPA and 20 mg kg −1 day −1 of DHA) enhanced muscle protein synthesis and suppressed protein breakdown signal during dexamethasone treatment in rats. Moreover, EPA has an anti‐inflammatory effect to decrease pro‐inflammatory cytokines (Castillero, Lopez‐Menduina, Martin, Villanua, & Lopez‐Calderon, ) and EPA administration suppresses TNF‐α production from macrophages (Calder, ; Sakuma & Yamaguchi, ).…”

“…Similarly,Fappi et al (2019) found that 30-days of n-3 PUFA supplementation (100 mg kg −1 day −1 of EPA and 20 mg kg −1 day −1 of DHA) enhanced muscle protein synthesis and suppressed protein breakdown signal during dexamethasone treatment in rats. Several studies have reported that EPA affects regulation of skeletal muscle mass.…”

“…Fish oil, containing high n-3 polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is the representative food component studied for maintenance of muscle mass. In the study of fish oil effect on muscle atrophy, several skeletal muscle atrophy models were used; cancer cachexia (Whitehouse, Smith, Drake, & Tisdale, 2001), acute starvation , sepsis (Khal & Tisdale, 2008), arthritis (Castillero, Martin, Lopez-Menduina, Villanua, & Lopez-Calderon, 2009), hindlimb immobilization (You, Park, Song, & Lee, 2010), energy restriction (Galmiche et al, 2016) and glucocorticoid (administration of dexamethasone) (Fappi et al, 2019). In these reports, fish oil intake facilitated muscle hypertrophy via activation of the protein synthesis pathway.…”

“…On the other hand, dietary fish oil also has effects on muscle atrophy. In the study of fish oil effect on muscle atrophy, several skeletal muscle atrophy models were used; cancer cachexia (Whitehouse, Smith, Drake, & Tisdale, ), acute starvation (Whitehouse & Tisdale, ), sepsis (Khal & Tisdale, ), arthritis (Castillero, Martin, Lopez‐Menduina, Villanua, & Lopez‐Calderon, ), hindlimb immobilization (You, Park, Song, & Lee, ), energy restriction (Galmiche et al, ) and glucocorticoid (administration of dexamethasone) (Fappi et al, ). However, the effect of fish oil on muscle atrophy induced by denervation treatment is unclear.…”