Abstract
Much is known about the positive effects of branched‐chain amino acids (BCAA) in regulating muscle protein metabolism. Comparatively much less is known about the effects of these amino acids and their metabolites in regulating myotube formation. Using cultured myoblasts, we showed that although leucine is required for myotube formation, this requirement is easily met by α‐ketoisocaproic acid, the ketoacid of leucine. We then demonstrated increases in the expression of the first two enzymes in the catabolism of the three BCAA, branched‐chain amino transferase (BCAT2) and branched‐chain α‐ketoacid dehydrogenase (BCKD), with ~3× increase in BCKD protein expression (p < .05) during differentiation. Furthermore, depletion of BCAT2 abolished myoblast differentiation, as indicated by reduction in the levels of myosin heavy chain‐1, troponin and myogenin. Supplementation of incubation medium with branched‐chain α‐ketoacids or related metabolites derivable from BCAT2 functions did not rescue the defects. However, co‐depletion of BCKD kinase partially rescued the defects. Collectively, our data indicate a requirement for BCAA catabolism during myotube formation and that this requirement for BCAT2 likely goes beyond the need for this enzyme to generate the α‐ketoacids of the BCAA.
Highlights
Branched-chain amino acids (BCAA: leucine, isoleucine, and valine) alone or in combination with resistance exercise have anabolic effects on skeletal muscle
We have demonstrated a requirement for appropriate regulation of BCAA catabolism for optimal muscle cell differentiation
While a requirement for leucine during differentiation might be expected since leucine is an essential amino acid, we have demonstrated that this requirement is met by provision of ketoisocaproic acid (KIC), the transamination product of leucine
Summary
Branched-chain amino acids (BCAA: leucine, isoleucine, and valine) alone or in combination with resistance exercise have anabolic effects on skeletal muscle. Mice with muscle specific deletion of BCKD kinase (BDK, the enzyme that catalyzes the inhibitory phosphorylation of the E1α subunit of BCKD), which would lead to elevated BCKD activity, have exaggerated muscle catabolic response to protein deficiency (Ishikawa et al, 2017) These studies underline the significance of appropriate regulation of muscle and whole body BCAA catabolism in organismic metabolism and response to stressors. When myotubes are formed, there is a change in the proteome such that there is an abundance of myofibrillar proteins, including myosin heavy chain, troponin, and tropomyosin Since these new proteins need to be synthesized de novo, and given the significance of BCAA in regulating protein turnover, it is reasonable to envisage a role for these amino acids during differentiation. In addition to reporting an increase in the levels of the first two enzymes in BCAA catabolic pathway during differentiation, we demonstrated a requirement for BCAT2 for optimal myotube formation and showed that this requirement likely goes beyond its ability to produce the α-ketoacids from the BCAA
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