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Recent Reviews Read, F1000 Factor 8.0

Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. Brault JJ, Jespersen JG, Goldberg AL. J Biol Chem. 2010 Jun 18; 285(25):19460-71

Evaluated by | David Marcinek and Kevin Conley, University of Washington, United States of America

Preventing muscle atrophy: is maintaining mitochondrial content not enough? This study shows that overexpression of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) transcriptional coactivators preserves mitochondrial content and prevents muscle atrophy, while stimulation of mitochondrial biogenesis with aminoimidazole carboxamide ribonucleotide (AICAR) does not prevent muscle loss.

There is great interest in developing pharmacological interventions to prevent muscle atrophy due to the increasing public health costs associated with skeletal muscle degeneration. PGC1alpha is a promising target because it stimulates mitochondrial biogenesis and prevents muscle atrophy in aging and disease {1,2}. Brault et al. find that PGC1alpha and beta expression prevent muscle atrophy following muscle denervation by inhibiting protein degradation, particularly by inhibiting increased expression of ubiquitin ligases, Atrogin1 and MuRF1. Administration of AICAR in vivo preserved PGC1alpha expression and mitochondrial content at control levels following muscle denervation. However, AICAR did not prevent muscle atrophy and had no effect on the expression of Atrogin1 and MuRF1 in denervated muscle. These results indicate that preserving mitochondrial content alone is not sufficient to prevent muscle atrophy. AICAR is an AMP analog that activates AMPK. Thus, administering AICAR sends the signal that the cell is experiencing chronic energy stress and results in chronic activation of AMPK. These results support the growing evidence that activation of AMPK may have pro-atrophy effects {1} that may counteract the anti-atrophy activity of PGC1alpha in skeletal muscle. Thus, any pharmacological intervention aimed at preventing muscle atrophy through a PGC1-related mechanism must account for parallel pathways regulated by energy metabolism.

Evaluated 16 November 2010