Beyond AICA riboside: In search of new specific AMP-activated protein kinase activators.

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA riboside) has been extensively used in vitro and in vivo to activate the AMP-activated protein kinase (AMPK), a metabolic sensor involved in both cellular and whole body energy homeostasis. However, it has been recently highlighted that AICA riboside also exerts AMPK-independent effects, mainly on AMP-regulated enzymes and mitochondrial oxidative phosphorylation (OXPHOS), leading to the conclusion that new compounds with reduced off target effects are needed to specifically activate AMPK. Here, we review recent findings on newly discovered AMPK activators, notably on A-769662, a nonnucleoside compound from the thienopyridone family. We also report that A-769662 is able to activate AMPK and stimulate glucose uptake in both L6 cells and primary myotubes derived from human satellite cells. In addition, A-769662 increases AMPK activity and phosphorylation of its main downstream targets in primary cultured rat hepatocytes but, by contrast with AICA riboside, does neither affect mitochondrial OXPHOS nor change cellular AMP:ATP ratio. We conclude that A-769662 could be one of the new promising chemical agents to activate AMPK with limited AMPK-independent side effects. (c) 2008 IUBMB IUBMB Life, 2008

Reduced muscle performance gain and hypertrophy and decrease in contractile

<p><b>machinery function following 2 month-ML in MDX mice.</b> Absolute muscle maximal force (a), muscle weight (b), muscle specific maximal force (c), specific maximal force of skinned muscle fibers (d), and muscle fatigue resistance (e) after 2 months of ML. a: significantly different from unoverloaded muscle (p<0.05). b: significantly different from corresponding C57 mice (p<0.05). n = 14–26/group for absolute and specific muscle maximal forces and n = 30/group (at least 7 per animal) for specific maximal force skinned fibers.</p

Restoration of the adaptive response to 1 month ML by dystrophin rescue.

<p>Absolute (a) and specific (b) muscle maximal forces, weight (c) and fatigue resistance (d) and after 1-month of ML combined with U7-mediated dystrophin rescue. a: significantly different from unoverloaded muscle (p<0.05). b: significantly different from corresponding C57 mice (p<0.05). c: significantly different from MDX+ML (p<0.05). n = 6/group.</p

Muscle histology following 2 month-ML in MDX mice.

<p>Fibrosis (a and b), percentage of centronucleated muscle fibers (c) and percentage of the different types of muscle fibers (d) after 2 months of ML. Representative images of fibrosis (red) on Sirius red staining cross-section (a) shown increased fibrosis in MDX and MDX+ML mice. Of note, since muscle fiber can express more than one MHC, the total percentage of the different muscle fiber types added up to well over 100%. n = 3–4/group for fibrosis and n = 5–8 for percentage of fibers. a: significantly different from unoverloaded muscle (p<0.05). b: significantly different from corresponding C57 mice (p<0.05).</p

Cellular aspects of the attenuation of muscle hypertrophy following 2 month-ML in MDX mice.

<p>Number (a and b) and diameter (c,d and e) of the muscle fibers after 2 months of ML. Of note, since muscle fiber can express more than one MHC, the sum of the number of the different types of muscle fibers exceeded the total number of fibers. The representative images (e) show reduced size of fibers expressing MHC-2b following ML. Cross-sections were revealed for MHC-2b (red), MHC-2a (green) and MHC-1 (blue) reactivity. Scale bar = 20 µm. a: significantly different from unoverloaded muscle (p<0.05). b: significantly different from corresponding C57 mice (p<0.05). n = 5–8/group.</p

Impaired adaptive response to mechanical overloading in dystrophic skeletal muscle

Dystrophin contributes to force transmission and has a protein-scaffolding role for a variety of signaling complexes in skeletal muscle. In the present study, we tested the hypothesis that the muscle adaptive response following mechanical overloading (ML) would be decreased in MDX dystrophic muscle lacking dystrophin. We found that the gains in muscle maximal force production and fatigue resistance in response to ML were both reduced in MDX mice as compared to healthy mice. MDX muscle also exhibited decreased cellular and molecular muscle remodeling (hypertrophy and promotion of slower/oxidative fiber type) in response to ML, and altered intracellular signalings involved in muscle growth and maintenance (mTOR, myostatin, follistatin, AMPKα1, REDD1, atrogin-1, Bnip3). Moreover, dystrophin rescue via exon skipping restored the adaptive response to ML. Therefore our results demonstrate that the adaptive response in response to ML is impaired in dystrophic MDX muscle, most likely because of the dystrophin crucial role