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Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation

Bert Blaauw^*,1, Marta Canato, Lisa Agatea^*,, Luana Toniolo, Cristina Mammucari, Eva Masiero^*,, Reimar Abraham^*, Marco Sandri^*,,, Stefano Schiaffino^*, and Carlo Reggiani^,

^* Venetian Institute of Molecular Medicine (VIMM), Padova, Italy;

Department of Human Anatomy and Physiology, and

Department of Biomedical Sciences, CNR Institute of Neurosciences, University of Padova, Padova, Italy; and

Dulbecco Telethon Institute, Rome, Italy

¹ Correspondence: Venetian Institute of Molecular Medicine, Via Orus 2, 35126 Padova, Italy. E-mail: bertblaauw{at}yahoo.com

A better understanding of the signaling pathways that control muscle growth is required to identify appropriate countermeasures to prevent or reverse the loss of muscle mass and force induced by aging, disuse, or neuromuscular diseases. However, two major issues in this field have not yet been fully addressed. The first concerns the pathways involved in leading to physiological changes in muscle size. Muscle hypertrophy based on perturbations of specific signaling pathways is either characterized by impaired force generation, e.g., myostatin knockout, or incompletely studied from the physiological point of view, e.g., IGF-1 overexpression. A second issue is whether satellite cell proliferation and incorporation into growing muscle fibers is required for a functional hypertrophy. To address these issues, we used an inducible transgenic model of muscle hypertrophy by short-term Akt activation in adult skeletal muscle. In this model, Akt activation for 3 wk was followed by marked hypertrophy (50% of muscle mass) and by increased force generation, as determined in vivo by ankle plantar flexor stimulation, ex vivo in intact isolated diaphragm strips, and in single-skinned muscle fibers. No changes in fiber-type distribution and resistance to fatigue were detectable. Bromodeoxyuridine incorporation experiments showed that Akt-dependent muscle hypertrophy was accompanied by proliferation of interstitial cells but not by satellite cell activation and new myonuclei incorporation, pointing to an increase in myonuclear domain size. We can conclude that during a fast hypertrophic growth myonuclear domain can increase without compromising muscle performance.—Blaauw, B., Canato, M., Agatea, L., Toniolo, L., Mammucari, C., Masiero, E., Abraham, R., Sandri, M., Schiaffino, S., Reggiani, C. Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation.

Key Words: BrdU • angiogenesis • skinned fibers • nuclear domain