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Role of β‐hydroxy‐β‐methylbutyrate (HMB) in leucine stimulation of muscle mitochondrial biogenesis
Author(s) -
Stancliffe Renee A,
Zemel Michael B
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.251.6
Subject(s) - leucine , mitochondrial biogenesis , mitochondrion , biogenesis , biochemistry , c2c12 , biology , metabolite , myocyte , chemistry , amino acid , microbiology and biotechnology , gene , myogenesis
We have previously demonstrated leucine to increase Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation in muscle cells. While the mechanism of these effects is not clear, it is likely that the leucine metabolites α‐ketoisocaproic acid (KIC) and HMB play a role. Dietary leucine is transaminated by branched‐chain aminotransferase (BCAT) to the α‐keto analogue (KIC), which is then metabolized into isovaleryl‐CoA or HMB by KIC‐dioxygenase. Approximately 5 to 10% of ingested leucine is converted into HMB. We have previously demonstrated that KIC and HMB both stimulate mitochondrial biogenesis and fatty acid oxidation similarly to leucine. To confirm that these effects of leucine are mediated by its metabolites, we knocked down KIC‐dioxygenase via siRNA transfection in C2C12 myoblasts and then determined the effect of intact leucine (0.5mM) versus HMB (50μM) on myoblast mitochondrial biogenesis (assessed fluorometrically via NAO binding). Both HMB and leucine increased mitochondrial biogenesis by ~30–35% (p<0.05) in the absence of KIC‐dioxygenase knock‐down. However, cells treated with siRNA failed to exhibit stimulation. Thus, leucine and KIC modulation of muscle mitochondrial biogenesis appear to be mediated by the leucine metabolite HMB.