The effect of caffeine on skeletal muscle anabolic signaling and hypertrophy

Abstract

Caffeine is a widely consumed stimulant with the potential to enhance physical performance through multiple mechanisms. However, recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. The primary purpose of this study was to assess the effect of caffeine on in vivo AMPK and mTOR pathway signaling, protein synthesis, and muscle growth. In cultured C2C12 muscle cells, physiological levels of caffeine failed to impact mTOR activation or myoblast proliferation or differentiation. We found that caffeine administration to mice did not significantly enhance the phosphorylation of AMPK or inhibit signaling proteins downstream of mTOR (p70S6k, S6, or 4EBP1) or protein synthesis after a bout of electrically stimulated contractions. Skeletal muscle-specific knockout of LKB1, the primary AMPK activator in skeletal muscle, on the other hand, eliminated AMPK activation by contractions and enhanced S6k, S6, and 4EBP1 activation before and after contractions. In rats, the addition of caffeine did not affect plantaris hypertrophy induced by the tenotomy of the gastrocnemius and soleus muscles. In conclusion, caffeine administration does not impair skeletal muscle load-induced mTOR signaling, protein synthesis, or muscle hypertrophy.

Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes

“…Given that >500 μM (100 mg/L) caffeine is considered to be potentially lethal for adult humans (Winek et al 2001), the caffeine concentration used in the present study likely represents the upper physiological limit of mammalian skeletal muscle. However, the caffeine dose used in the present study is very similar to those of previous investigations (Lewis et al 1982; Goodman 1987; Egawa et al 2011a, b; Moore et al 2017). As previously mentioned, Lewis et al (1982) and Goodman (1987) discovered that treating rat EDL muscle with 4–10 mM caffeine significantly reduced protein synthesis.…”

“…As previously mentioned, Lewis et al (1982) and Goodman (1987) discovered that treating rat EDL muscle with 4–10 mM caffeine significantly reduced protein synthesis. A recent investigation by Moore et al (2017) revealed that supplementing drinking water with 1 g/L caffeine (5.0 mM) did not affect protein synthesis or growth of the plantaris muscle from rats 2-weeks after sham or synergist ablation surgery. A further consideration is the half-life of caffeine in rodents vs. humans.…”

The Influence of Caffeine Supplementation on Resistance Exercise: A Review

“…Moreover, caffeine even enhanced the phosphorylation of ribosomal protein S6 suggesting a positive effect of caffeine on anabolic signaling. Furthermore, work on rats in the same study showed that caffeine did not affect plantaris muscle hypertrophy [91]. While cell culture and animal models may provide some interesting findings, they also may have limited relevance to humans.…”

“…Some of the studies conducted in cultured cells have observed that caffeine inhibited mTOR activity [89,90], albeit, such effects were seen at supra-physiological concentrations of caffeine. A recent study by Moore et al [91] conducted in mice (with physiological concentrations of caffeine that would be observed in humans following moderate caffeine intake), showed that caffeine did not negatively affect mTOR activity or muscle protein synthesis after a bout of electrically-stimulated contractions. Moreover, caffeine even enhanced the phosphorylation of ribosomal protein S6 suggesting a positive effect of caffeine on anabolic signaling.…”

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration

“…LKB1 knockout in skeletal muscle results in a nearly complete elimination of basal, exercise, and AICAR-induced AMPKα2 activity [ 14 , 18 , 19 ] and overall AMPK phosphorylation [ 13 , 16 , 108 , 109 , 110 ], while it has little [ 13 , 14 ] to no [ 17 , 18 ] effect on AMPKα1 activity, which is an important consideration since AMPKα1 seems to be the major isoform regulating muscle growth [ 78 , 80 ]. LKB1 also phosphorylates several other AMPK family members, at least one of which, sucrose non-fermenting 1 AMPK related kinase (SNARK) is important in the maintenance of muscle mass [ 111 ].…”