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

Abstract

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 ( approximately 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.

Systematic review of the synergist muscle ablation model for compensatory hypertrophy

“…Twenty-four papers were review articles; 7,9, eight studies used a model other than the ablation of synergists to cause hypertrophy; [43][44][45][46][47][48][49][50] and six were in vitro studies. [51][52][53][54][55][56] All these studies were excluded. Among the remaining 25 studies, seven did not compare the cross-sectional area of the muscle and/or muscle mass to a control group and were excluded.…”

Muscle memory and a new cellular model for muscle atrophy and hypertrophy

“…More recently, the debate was rejuvenated by several transgenic models displaying large fibres without a corresponding increase in the number of myonuclei, such as mice overexpressing the proteins Ski (Bruusgaard et al, 2005), Akt (Blaauw et al, 2009) or junB (Raffaello et al, 2010), as well as myostatin-null mice (Amthor et al, 2009). However, for Ski and myostatin the hypertrophy is not fully functional, as the specific force is reduced (Amthor et al, 2007;Charge et al, 2002;Mendias et al, 2011).…”

“…Akt mice seemed to have normal specific force after 3 weeks of overexpression (Blaauw et al, 2009), but it is unclear whether this condition is sustainable over longer periods (Blaauw and Reggiani, 2014). Similarly, specific force appeared normal after 2 weeks of overload hypertrophy in mice where 90% of satellite cells were ablated using an inducible Pax7-diphtheria toxin transgene (McCarthy et al, 2011).…”

Is Sarcomere Lattice Geometry Optimal? Analysis of Several Potential Virtual Polygon Cross‐Sectional Patterns for Actin and Myosin Myofilaments in Muscle

“…This belief is based on the assumption that each of the muscle cell's multiple nuclei can only support a certain volume of cytoplasm (Bruusgaard et al, 2010;McCarthy et al, 2011). These studies, using overloaded muscle, present new experimental data supporting the view that this hypertrophy can occur independently of satellite cell involvement (Amthor et al, 2009;Blauuw et al, 2009;Bruusgarrd et al, 2010;McCarthy et al, 2011). As muscle hypertrophy absolutely requires new myofilaments of actin and myosin, it seems relevant to ask the question: Where might they be inserted and organized into new functional structural units within the sarcomere lattice geometry?…”