Atrophy of S6K1−/− skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control

Abstract

The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1(-/-) myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…Consistently, in the past literature, mTOR activation has been described to be prerequisite for myogenic differentiation and growth. 31 Second, we observed that mutations in the EGFR were accompanied by constitutive activation of the mTOR cassette proteins, namely mTOR-S6K/4E-BP1. However, these exceptional cases harboring EGFR mutation aside, the data here suggest that in the majority of the cases, mTOR activation may be largely independent of EGFR signaling.…”

Mitochondrial energetic metabolism: A simplified model of TCA cycle with ATP production

“…1 The concentrations listed in table 1 are all given in mM, whereas in the referenced articles they are often given in μmole/(g fresh weight), μmole/(g dry weight) or μmole/(g protein). In order to have all those concentrations in mM, we collected values that gave us an idea of the converting factors: we used literature values for the ratio dry weight/fresh weight [55,3,23,36,5,49,9,45,52], cell volumes [34,43,39,13,47,40,7,33], and values for the ratio cytoplasm volume/dry weight [45]. Even though these values were determined for different organisms, the average should be a good approximation.…”

“…Local existence and uniqueness on some maximal time interval is straightforward by using the CauchyLipschitz theorem. Since the initial conditions are non-negative, and the vector field defined by the right hand side of (31)(32)(33)(34)(35)(36)(37) at the boundary of the region I R 7 + never points outwards, all the concentrations p, · · · , n remain non-negative for all τ.…”

Regulation of catalytic activity of S6 kinase 2 during cell cycle

“…Both S6K1 and S6K2 are regulated by the same phosphoinositide-3-kinase (PI3K)/Akt/mTOR pathways [8]. S6K1 plays a role in cell size control; cells from the S6K1-null or S6K1/S6K2 double-null mice are smaller than those from the wildtype mice, and re-expression of S6K1, but not S6K2, in the double-null cells restores the normal size, indicating that S6K1 and S6K2 have non-overlapping cellular functions [1,9,10]. Data also suggest that the two kinases share some functions; both S6K1 and S6K2 can phosphorylate the 40S ribosomal protein S6 [10,11].…”