A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification

Abstract

Nerve activity controls fiber size and fiber type in skeletal muscle, but the underlying molecular mechanisms remain largely unknown. We have previously shown that Ras-mitogen-activated protein kinase and calcineurin control fiber type but not fiber size in regenerating rat skeletal muscle. Here we report that constitutively active protein kinase B (PKB), also known as Akt, increases fiber size and prevents denervation atrophy in regenerating and adult rat muscles but does not affect fiber type profile. The coexistence of hypertrophic muscle fibers overexpressing activated PKB with normal-size untransfected fibers within the same muscle points to a cell-autonomous control of muscle growth by PKB. The physiological role of this pathway is confirmed by the finding that PKB kinase activity and phosphorylation status are significantly increased in innervated compared with denervated regenerating muscles in parallel with muscle growth. Muscle fiber hypertrophy induced by activated PKB and by a Ras double mutant (RasV12C40) that activates selectively the phosphoinositide 3-kinase-PKB pathway is completely blocked by rapamycin, showing that the mammalian target of rapamycin kinase is the major downstream effector of this pathway in the control of muscle fiber size. On the other hand, nerve activity-dependent growth of regenerating muscle is only partially inhibited by dominant negative PKB and rapamycin, suggesting that other nerve-dependent signaling pathways are involved in muscle growth. The present results support the notion that fiber size and fiber type are regulated by nerve activity through different mechanisms.

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

“…These data demonstrated an activation of the PI3K/Akt signalling pathway in response to MSTN loss-of-function in cattle as previously shown in mice. They are in agreement with data indicating a crucial role of this pathway in muscle hypertrophy (Glass, 2003) for example, increase in fibre size induced by constitutive activation of Akt (Pallafacchina et al, 2002) and hypertrophy of type IIb muscle fibres induced by muscle-specific Akt1 transgene expression (Izumiya et al, 2008).…”

Insulin and Wnt1 Pathways Cooperate to Induce Reserve Cell Activation in Differentiation and Myotube Hypertrophy

“…Here, we focused on the serine/threonine kinase GSK-3, a major substrate phosphorylated and down-regulated by PKB/Akt in a number of cellular systems (Cross et al, 1995). Its inhibition via the PI3K-PKB/Akt signaling cascade has recently been shown to play an important role in IGF-induced myotube hypertrophy (Rommel et al, 2001;Vyas et al, 2002;Pallafacchina et al, 2002) and in overloaded skeletal muscle . We show here that GSK-3 activity is down-regulated in differentiating myotubes because the basal phosphorylation of GSK-3 increases between proliferative C2.7 myoblasts and differentiated myotubes but not in reserve cells, further supporting that GSK-3 inhibition plays an integral role in the process of muscle differentiation.…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…It has been reported that activated calcineurin mediates the hypertrophic effect of IGF-1 (Musarò et al, 1999;Semsarian et al, 1999). However, there is compelling evidence, including transgenic and knock-out data, to show that calcineurin has no effect on muscle hypertrophy but that the hypertrophic effect of IGF-1 is mediated by the PI3K pathway as detailed earlier (Naya et al, 2000;Bodine et al, 2001b;Rommel et al, 2001;Pallafacchina et al, 2002). Calcineurin is activated by raised intracellular calcium, triggered by extracellular signals like nervous impulses, or hormonal input, such as IGF-1 stimulation.…”