Mice Deficient in Ribosomal Protein S6 Phosphorylation Suffer from Muscle Weakness that Reflects a Growth Defect and Energy Deficit

RUVINSKY IGOR; M. KATZ; AVIGAIL DREAZEN; YUVAL GIELCHINSKY; A. SAADA-REISCHNN ; NANETTE FREEDMAN; EYAL MISHANI; GABRIEL ZIMMERMAN; JUDITH KASIR; ODED MEYUHAS

PLOS ONE

PUBLIC LIBRARY SCIENCE

Año: 2009 vol. 4 p. 5618 - 5618

1932-6203

AbstractBackground: Mice, whose ribosomal protein S6 cannot be phosphorylated due to replacement of all five phosphorylatableserine residues by alanines (rpS6P2/2), are viable and fertile. However, phenotypic characterization of these mice andembryo fibroblasts derived from them, has established the role of these modifications in the regulation of the size of severalcell types, as well as pancreatic b-cell function and glucose homeostasis. A relatively passive behavior of these mice hasraised the possibility that they suffer from muscle weakness, which has, indeed, been confirmed by a variety of physicalperformance tests.Methodology/Principal Findings: A large variety of experimental methodologies, including morphometric measurementsof histological preparations, high throughput proteomic analysis, positron emission tomography (PET) and numerousbiochemical assays, were used in an attempt to establish the mechanism underlying the relative weakness of rpS6P2/2muscles. Collectively, these experiments have demonstrated that the physical inferiority appears to result from two defects:a) a decrease in total muscle mass that reflects impaired growth, rather than aberrant differentiation of myofibers, as well asa diminished abundance of contractile proteins; and b) a reduced content of ATP and phosphocreatine, two readilyavailable energy sources. The abundance of three mitochondrial proteins has been shown to diminish in the knockinmouse. However, the apparent energy deficiency in this genotype does not result from a lower mitochondrial mass orcompromised activity of enzymes of the oxidative phosphorylation, nor does it reflect a decline in insulin-dependentglucose uptake, or diminution in storage of glycogen or triacylglycerol (TG) in the muscle.Conclusions/Significance: This study establishes rpS6 phosphorylation as a determinant of muscle strength through its rolein regulation of myofiber growth and energy content. Interestingly, a similar role has been assigned for ribosomal protein S6kinase 1, even though it regulates myoblast growth in an rpS6 phosphorylation-independent fashion.