Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the antidiabetes drug berberine.
OBJECTIVE
Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses.


METHODS
We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism.


RESULTS
Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator-activated receptor gamma coactivator-1alpha, berberine-induced changes in muscle protein metabolism were prevented.


CONCLUSIONS
Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy.
Wang
Huiling
H
Renal Division, Jimin Hospital, Shanghai, People's Republic of China.
Liu
Dajun
D
Cao
Peirang
P
Lecker
Stewart
S
Hu
Zhaoyong
Z
D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D017931:DNA Primers; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000139:chemically induced; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
D017931:DNA Primers; D007004:Hypoglycemic Agents; D009124:Muscle Proteins; D014157:Transcription Factors; D001599:Berberine; D012313:RNA; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases