Excess branched-chain amino acids alter myotube metabolism and substrate preference which is worsened by concurrent insulin resistance

Branched‐chain amino acid supplementation suppresses the detraining‐induced reduction of mitochondrial content in mouse skeletal muscle

“…60 BCAA at supraphysiologically high levels (20 mM) reduced mitochondrial function in C2C12 myotubes. 24 Therefore, there was a concern that inhibition of the degradation process by BCAA suppressed mitochondrial clearance and caused the accumulation of low-quality mitochondria. In this study, we assessed Complexes II-driven state II (IV) and III respiration and found no difference.…”

“…23 On the other hand, BCAA at supraphysiologically high levels (20 mM) decreases mitochondrial function in C2C12 myotubes. 24 Therefore, the effect of BCAA on mitochondrial function has been controversial. Thus, the purpose of this study was to clarify the effects of BCAA supplementation on mitochondrial adaptations in skeletal muscle during detraining.…”

Branched‐Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary

“…↑CS activity, oxygen consumption, ATP production D'Antona 2016 [65] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 1 %wt:vol + Rvs 50 μM, 24 h ↑/rescued CS activity, oxygen consumption, ATP production D'Antona 2016 [65] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 0.2 mM Leu content, 6 days ↔Ppargc1a, Nrf1, Tfam, Cs, Atp5b, ↓Cox5a mRNA expression; ↔mitochondrial content/basal and peak respiration Rivera 2021 [66] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 2 mM Leu content, 6 days ↔Ppargc1a, Nrf1, Tfam, Cs, Cox5a, Atp5b mRNA expression; ↑mitochondrial content ↔basal and peak respiration Rivera 2021 [66] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 20 mM Leu content, 6 days ↔Ppargc1a, Nrf1, Tfam, Cs, Cox5a, Atp5b mRNA expression; ↑mitochondrial content ↔basal ↓peak respiration Rivera 2021 [66] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 0.2 mM Leu content, 6 days + IR ↔Ppargc1a, Nrf1, Tfam, Cs, Atp5b, ↓Cox5a mRNA expression; ↔mitochondrial content/basal and peak respiration Rivera 2021 [66] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 2 mM Leu content, 6 days + IR ↔Ppargc1a, Nrf1, Tfam, Cs, Atp5b, ↓ Cox5a mRNA expression; ↔mitochondrial content/basal and peak respiration Rivera 2021 [66] C2C12 myotubes BCAA 2:1:1 (Leu:Ile:Val) 20 mM Leu content, 6 days + IR ↔Nrf1, Tfam, Cs, Atp5b, ↓ Ppargc1a, Cox5a mRNA expression; ↔mitochondrial content/basal and peak respiration Rivera 2021 [66] HL-1 cardiomyocytes BCAA 2:1:1 (Leu:Ile:Val,) 48 h ↑Ppargc1a, Nrf1, Tfam, Cytc, Coxiv, Sirt1 mRNA expression; ↑SIRT1 protein expression; ↑mtDNA, ATP content D'Antona 2010 [33] HL-1 cardiomyocytes BCAA 2:1:1 (Leu:Ile:Val) 1 %wt:vol, 48 h ↑Ppargc1a, ↔Nrf1, Tfam, Cytc, Coxiv mRNA expression Tedesco 2020 [55] HL-1 cardiomyocytes 𝛼5 (BCAA mixture) 1 %wt:vol, 48 h ↑Ppargc1a, Nrf1, Tfam, Cytc, Coxiv mRNA expression; ↑COX IV, ↔Cyt C protein expression; ↑CS activity Tedesco 2020 [55] (Continued) ↑/rescued Cytc, Coxiv, ↔Ppargc1a, Nrf1, Tfam mRNA expression Tedesco 2020 [55] HL-1 cardiomyocytes Tedesco 2020 [55] Mouse primary cardiomyocytes BCAA 2:1:1 (Leu:Ile:Val) 0.208, 0.416, 0.832, 1.664 mM, 12 h ↑Ppara, Acaa2, Acadm, Cd36, Cpt1 mRNA expression; ↑PPAR𝛼 protein expression; ↑PAM oxidation…”

“…[ 29 ] C2C12 myotubes treated with a wide‐continuum of BCAA concentrations at a ratio of 2:1:1 showed increased mitochondrial staining at 2 and 20 mM (per leucine content) but not 0.2 mM, suggesting a dose‐dependency. [ 66 ] Perplexingly, 20‐mM‐treated cells displayed reduced basal mitochondrial respiration. Moreover, the addition of insulin resistance diminished the increase in mitochondrial staining by BCAA treatment, and reduced basal and peak mitochondrial respiration, as well as caused a significant reduction in Ppargc1a , Cs , Cox5a , and Atp5b .…”

“…Moreover, the addition of insulin resistance diminished the increase in mitochondrial staining by BCAA treatment, and reduced basal and peak mitochondrial respiration, as well as caused a significant reduction in Ppargc1a , Cs , Cox5a , and Atp5b . [ 66 ] Another study using isolated mouse primary cardiomyocytes showed either leucine or valine, or their alpha‐ketoic acid derivatives KIC or alpha‐ketoisovalerate (KIV), respectively, or a BCAA mixture dose‐dependently increased mitochondrial fatty acid oxidation and peroxisome proliferator‐activated receptor alpha (PPARα) protein expression in a dose‐dependent fashion, which was accompanied by increased carnitine palmitoyl transferase 1b (CPT1B) and fatty acid translocase expression but not PGC‐1α (please see table for specific treatment concentrations). [ 59 ] Conversely, neither isoleucine or the alpha‐ketoic acid derivative of isoleucine, α‐keto‐β‐methylvalerate (KMV) altered PPARα expression or fatty acid oxidation.…”