Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy

Abstract

Skeletal muscle atrophy is a severe morbidity caused by a variety of conditions, including cachexia, cancer, AIDS, prolonged bedrest, and diabetes. One strategy in the treatment of atrophy is to induce the pathways normally leading to skeletal muscle hypertrophy. The pathways that are sufficient to induce hypertrophy in skeletal muscle have been the subject of some controversy. We describe here the use of a novel method to produce a transgenic mouse in which a constitutively active form of Akt can be inducibly expressed in adult skeletal muscle and thereby demonstrate that acute activation of Akt is sufficient to induce rapid and significant skeletal muscle hypertrophy in vivo, accompanied by activation of the downstream Akt/p70S6 kinase protein synthesis pathway. Upon induction of Akt in skeletal muscle, there was also a significant decrease in adipose tissue. These findings suggest that pharmacologic approaches directed toward activating Akt will be useful in inducing skeletal muscle hypertrophy and that an increase in lean muscle mass is sufficient to decrease fat storage.

Resistance to body fat gain in ‘double-muscled’ mice fed a high-fat diet

“…Alternatively, myostatin has been observed to promote adipogenesis in multipotential mesenchymal cells, suggesting that loss of myostatin function may directly suppress adipocyte differentiation. 9 Our results are consistent with these in vitro findings; however, it is also known that other mouse models showing increased muscle mass, such as transgenic mice overexpressing IGF-1, 10,11 Akt, 12 and ski 13 show decreased fat mass. It is therefore possible that an indirect effect of double-muscling on fat metabolism may also be involved in the resistance to body fat accumulation in the myostatin-deficient animals; however, indirect calorimetry studies have found no significant differences in the respiratory exchange ratio between normal mice and myostatin-deficient rodents.…”

PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

“…Moreover, in addition to acting as an inductive cue for hypertrophy, activation of the Akt/mTOR pathway could also prevent muscle atrophy in vivo. 30,32,33,43 Furthermore, it has been shown in vitro that the overexpression of Src homology 2 domain-containing inositol-5Ј-phosphatase 2, which like PTEN decreases PiP 3 level, led to atrophy, whereas the overexpression of a dominant negative mutant, which increases PiP 3 level, induced hypertrophy. 32 The overexpression of inositol-5Ј-phosphatase 2 in healthy mice muscle had no effect on fiber size but the overexpression of the phosphatase in a model of compensatory hypertrophy completely blocked the hypertrophy response.…”

IGF-1 is downregulated in experimental cancer cachexia

“…Active Akt has been found significantly reduced in different models of skeletal muscle atrophy, such as unloading and denervation (50), whereas transgenic mice overexpressing Akt are protected against denervation-induced muscle atrophy (7). Hyperexpression of Akt in skeletal muscle cells or its conditional activation in the skeletal muscle of adult rats results in a hypertrophic phenotype (39,47). Not only does activation of Akt stimulate protein synthesis through regulation of glycogen synthase kinase-3␤ and mTOR (mammalian target of rapamycin) kinases (7), but it also may downregulate protein breakdown.…”