Mammalian Target of Rapamycin (mTOR) Signaling Network in Skeletal Myogenesis

Abstract

Mammalian (or mechanistic) target of rapamycin (mTOR)regulates a wide range of cellular and developmental processes by coordinating signaling responses to mitogens, nutrients, and various stresses. Over the last decade, mTOR has emerged as a master regulator of skeletal myogenesis, controlling multiple stages of the myofiber formation process. In this minireview, we present an emerging view of the signaling network underlying mTOR regulation of myogenesis, which contrasts with the well established mechanisms in the regulation of cell and muscle growth. Current questions for future studies are also highlighted.

Modulating myosin restores muscle function in a mouse model of nemaline myopathy

“…The regulation of muscle fiber size is influenced by the balance between rates of protein degradation and synthesis 23. Hence, to gain insight into the underlying causes of the increased CSA with rAAV6:MYL4, we sought to determine whether increased muscle fiber size was a function of altered signaling via the Akt‐mTOR pathway, a major determinant of protein turnover in muscle 24. We did not detect differences in the expression or activation of the upstream element PI3‐kinase, or in the activation of Akt and mTOR as determined from the p‐Akt to Akt and p‐mTOR to mTOR ratios (Fig 5).…”

mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration

“…Although the antiinflammatory and antifibrotic effects of rapamycin make this an enticing option to treat patients with muscle injury, studies have shown that mTOR inhibition actually has a detrimental effect on muscle size after injury (2,30,36). Other studies have shown that BMP signaling has a positive effect on myofiber size and satellite cell expansion (3,5).…”

“…Rapamycin has been shown to reduce fibrosis in several tissue types (21)(22)(23)(24)(25)(26)(27)(28). However, in the setting of muscle injury, this comes at a cost, as mTOR/AKT signaling regulates myofiber size (2,30). Previous studies that shown that, while the early phases of muscle regeneration proceed with rapamycin, myofiber growth is halted (38).…”

“…We have also previously shown that rapamycin eliminates ectopic bone in a genetic model of hyperactive BMP signaling (29). However, studies have also shown that when administered in models of muscle trauma, rapamycin causes unwanted muscle atrophy (2,30). Therefore, a strategy to eliminate the adverse effects associated with rapamycin and loss of mammalian target of rapamycin (mTOR) at sites of muscle injury, while achieving the reduced fibrosis and pathologic mesenchymal cell presence at sites of muscle injury would make rapamycin an attractive clinical option for patients with muscle trauma.…”

mTORCing about myogenic differentiation

“…1 This rapamycin-sensitive inhibition of myogenesis has been extensively reviewed elsewhere. 2 The mTOR kinase is present in the cell within 2 complexes, the rapamycin sensitive mTORC1 which contains Raptor (Fig. 1, lower panel), and the rapamycin insensitive mTORC2 complex which contains Rictor (for a recent review of this vast subject see 3 ).…”