Clenbuterol, a β2-adrenergic Agonist, Reciprocally Alters PGC-1 Alpha and RIP140 and Reduces Fatty Acid and Pyruvate Oxidation in Rat Skeletal Muscle

Am J Physiol Regul Integr Comp Physiol. 2012 Feb 1;302(3):R373-84. doi: 10.1152/ajpregu.00183.2011. Epub 2011 Nov 9.

Abstract

Clenbuterol, a β2-adrenergic agonist, reduces mitochondrial content and enzyme activities in skeletal muscle, but the mechanism involved has yet to be identified. We examined whether clenbuterol-induced changes in the muscles' metabolic profile and the intrinsic capacity of mitochondria to oxidize substrates are associated with reductions in the nuclear receptor coactivator PGC-1 alpha and/or an increase in the nuclear corepressor RIP140. In rats, clenbuterol was provided in the drinking water (30 mg/l). In 3 wk, this increased body (8%) and muscle weights (12-17%). In red (R) and white (W) muscles, clenbuterol induced reductions in mitochondrial content (citrate synthase: R, 27%; W, 52%; cytochrome-c oxidase: R, 24%; W, 34%), proteins involved in fatty acid transport (fatty acid translocase/CD36: R, 36%; W, 35%) and oxidation [β-hydroxyacyl CoA dehydrogenase (β-HAD): R, 33%; W, 62%], glucose transport (GLUT4: R, 8%; W, 13%), lactate transport monocarboxylate transporter (MCT1: R, 61%; W, 37%), and pyruvate oxidation (PDHE1α, R, 18%; W, 12%). Concurrently, only red muscle lactate dehydrogenase activity (25%) and MCT4 (31%) were increased. Palmitate oxidation was reduced in subsarcolemmal (SS) (R, 30%; W, 52%) and intermyofibrillar (IMF) mitochondria (R, 17%; W, 44%) along with reductions in β-HAD activity (SS: R, 17%; W, 51%; IMF: R, 20%; W, 57%). Pyruvate oxidation was only reduced in SS mitochondria (R, 20%; W, 28%), but this was not attributable solely to PDHE1α, which was reduced in both SS (R, 21%; W, 20%) and IMF mitochondria (R, 15%; W, 43%). These extensive metabolic changes induced by clenbuterol were associated with reductions in PGC-1α (R, 37%; W, 32%) and increases in RIP140 (R, 23%; W, 21%). This is the first evidence that clenbuterol appears to exert its metabolic effects via simultaneous and reciprocal changes in the nuclear receptor coactivator PGC-1α and the nuclear corepressor RIP140.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Animals
  • Clenbuterol / pharmacology*
  • Down-Regulation / drug effects
  • Fatty Acids / metabolism*
  • Male
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Mitochondrial Proteins / drug effects
  • Mitochondrial Proteins / metabolism
  • Models, Animal
  • Muscle Proteins / drug effects
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Interacting Protein 1
  • Oxidation-Reduction
  • Palmitates / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Pyruvates / metabolism*
  • RNA-Binding Proteins / drug effects
  • RNA-Binding Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism*
  • Up-Regulation / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Adrenergic beta-2 Receptor Agonists
  • Fatty Acids
  • Mitochondrial Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Nuclear Receptor Interacting Protein 1
  • Palmitates
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Pyruvates
  • RNA-Binding Proteins
  • Transcription Factors
  • Clenbuterol