Phenotype Selection Reveals Coevolution of Muscle Glycogen and Protein and PTEN as a Gate Keeper for the Accretion of Muscle Mass in Adult Female Mice

Abstract

We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice) characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold) if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK), were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α) and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß) and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.

Skeletal muscle cellularity and glycogen distribution in the hypermuscular Compact mice

“…The phenotype selection on extreme muscle mass in DU6P mice revealed the co-evolution of high glycogen and protein content of the muscle. 25 This finding is in line with our observation on the simultaneous increase of protein and glycogen contents in Compact muscle. The PI3K/Akt signaling plays a central role in integrating anabolic and catabolic responses in skeletal muscle influencing muscle mass.…”

“…The PI3K/Akt signaling plays a central role in integrating anabolic and catabolic responses in skeletal muscle influencing muscle mass. 26 , 27 PTEN (Phosphatase and tensin homolog) negatively affects the PI3K/Akt pathway; 28 moreover, Sawitzky and colleagues 25 identified PTEN as a gate keeper molecule in the co-evolutionary regulation of high glycogen and protein content.…”

Maternal and Paternal Genomes Differentially Affect Myofibre Characteristics and Muscle Weights of Bovine Fetuses at Midgestation

“…This imprinted gene has been identified as a QTL for postnatal muscle mass [31], [60] and encodes a miRNA in intron 2 that targets transcripts of the non-imprinted IGF1 gene [61]. Several other genes in this pathway, including PTEN , a gatekeeper for the accretion of muscle mass [7], are also targeted by miRNAs [13], [62]. The significance of allelic differences in miRNA target sequences for regulation of muscle mass by epistatic miRNA interference has been demonstrated with myostatin alleles in the ovine model [26].…”

“…It is a major source of endocrine factors, including insulin-like growth factors -I (IGF1) and -II (IGF2), key components of the insulin-like growth factor (IGF) system and growth hormone – IGF axis, which are major regulators of pre- and postnatal muscle development and growth [4]–[7]. Skeletal muscle is composed of two major fibre types, type I (slow oxidative) fibres and type II (fast) fibres [2].…”

Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

“…Skeletal muscle function is partially controlled by the Akt/mammalian Target of Rapamycin Complex 1 (mTORC1) pathway. Akt/mTORC1 regulates both skeletal muscle mass and metabolism via activation of several ATP-demanding processes such as protein synthesis [ 15 ], glycogen storage [ 16 , 17 ], and mitochondrial biogenesis [ 18 ]. The Akt/mTOR pathway also controls mitochondrial function by fostering the interaction between mitochondria and the endoplasmic reticulum (ER) in the mitochondria-associated membranes compartment (MAMs) [ 19 ].…”