Project description:Malnutrition and low muscle mass (sarcopenia) are common problems in patients with cancer. However, a low muscle mass is associated with negative clinical outcomes in patients with cancer. Therefore, it is very important to maintain muscle mass in this population. This study aims to investigate the effect of an oral nutritional supplement on skeletal muscle mass during anti-cancer treatment.
Project description:Skeletal muscle mass is an important determinant of whole-body glucose disposal. We here show that mice (M-PDK1KO mice) with skeletal muscle–specific deficiency of 3'-phosphoinositide–dependent kinase 1 (PDK1), a key component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of exercise load–induced muscle hypertrophy. Whereas exercise load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by exercise load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of protein synthesis via the S6K-S6 axis.
Project description:In this study, we show that muscle-specific inactivation of FBXW7 elicits striking defects in postprandial glucose metabolism and failure to maintain skeletal muscle mass in adult mice. Further, mice lacking FBXW7 exhibited impaired endurance capacity and exacerbated HFD-induced insulin resistance and postprandial hyperglycemia. At the mechanistic level, RNAseq and quantitative proteomic analysis revealed global effects of FBXW7 deficiency on skeletal muscle transcriptome and proteome. This work illustrates a prominent role of FBXW7 in integrating postprandial nutritional signals to coordinate glucose metabolism and muscle mass maintenance.
Project description:The female sex hormone estrogens plays a critical role in maintaining muscle mass and muscle stem cell (MuSCs) functions. However, it is still unclear about downstream pathways of estrogens including its receptors that are expressed in both skeletal muscle tissue and MuSCs. To study the specific role of estrogen receptor β (ERβ), one of two main types of estrogen receptors, in skeletal muscle and MuSCs, we generated muscle-specific ERβ-knockout (mKO) mice and muscle stem cell-specific ERβ-knockout (scKO) mice. Here, we show that muscle-specific ERβ-deficient induced decreased muscle strength and fast-type muscle mass in young female mice. Furthermore, muscle stem cell-specific ERβ-deficient young female mice but not male exhibited impaired muscle regeneration ability after acute muscle injury, accompanied by a decreased proliferation rate of muscle stem cells. RNA sequencing analysis showed that the loss of ERβ in muscle stem cells changes the expression of cell cycle associated genes and niche component factors including laminin and collagen. Thus, our characterization of mKO and scKO mice indicate that the estrogen-ERβ pathway is a sex-specific regulatory mechanism that controls both skeletal muscle mass and the proliferation of muscle stem cell in females and could be of importance in a therapeutic context.
Project description:We propose that neuroinflammation and skeletal muscle interaction in intermittent restraint stress regulate skeletal muscle mass through a defined mechanism.
Project description:Muscle atrophy contributes to the poor prognosis of many physiopathological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca2+] which control aerobic metabolism, cell death and survival pathways. We have investigated in vivo the effects of mitochondrial Ca2+ homeostasis in skeletal muscle function and trophism, by overexpressing or silencing the Mitochondrial Calcium Uniporter (MCU). The results coherently demonstrate that both in developing and in adult muscles MCU-dependent mitochondrial Ca2+ uptake has a marked trophic effect that does not depend on autophagy or aerobic control, but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1M-NM-14 and Igf1-Akt/PKB. In adult mice, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca2+-dependent organelle-to-nucleus signaling route, which links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in sarcopenia. Experiments were performed on biological replicates of single skeletal muscle fibres. Seven fibres were chosen for their Mutochondrial Calcium Uniporter (MCU) overexpression and other seven fibres because MCU was silenced. Overexpression and silencing were performed injecting skeletal muscle with AAV containing MCU gene or short interfering oligos specific for MCU. As control was profiled eigth fibres transfected with AAV and eigth wild type fibres. Analyses were performed 7 days and 14 days after the AAV injection (3 fibers after 7 days and 4 fibers after 14 days for MCU overexpression and silencing, four fibres after 7 days and four after 14 days for control).