Objectives: Acute muscle wasting in the critically ill is common, and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass: insulin-like growth factor-1 (IGF-1), myostatin and growth and differentiation factor-15 (GDF-15), were measured over a week. It was hypothesised that patients who developed acute muscle wasting would show distinct patterns of change in these mediators.Design: A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting.Setting: Tertiary cardiothoracic referral centre: Royal Brompton Hospital, London, UK.Patients: 42 patients undergoing elective high-risk cardiothoracic surgery.Interventions: Circulating IGF-1, myostatin and GDF-15 were assayed pre-operatively and over the first week post-operatively. The ability of GDF-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. Measurements and main results: 23 of 42 patients (55%) developed quadriceps atrophy. There wasan acute decrease in IGF-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma GDF-15 concentrations increased in all patients. This increase in GDF-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the non-wasting group (p>0.05). IGF-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p<0.01) but did in the nonwasting group (p>0.05). Finally, we demonstrated that GDF-15 caused atrophy of myotubes in vitro. Conclusion:These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. GDF-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with Intensive care unit acquired paresis and other forms of acute muscle wasting.Abstract word count: 292

BackgroundA loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis, so changes in the control of ribosome synthesis are potential contributors to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR‐424‐5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).MethodsTargets of miR‐424‐5p were identified by Argonaute2 pull down, and the effects of the miRNA on RNA and protein expression were determined by quantitative polymerase chain reaction and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over‐expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by quantitative polymerase chain reaction in patients with COPD and intensive care unit (ICU)‐acquired weakness and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.ResultsPull‐down assays showed that miR‐424‐5p bound to messenger RNAs encoding proteins associated with muscle protein synthesis. The most highly enriched messenger RNAs encoded proteins required for the Pol I RNA pre‐initiation complex required for ribosomal RNA (rRNA) transcription, (PolR1A and upstream binding transcription factor). In vitro, miR‐424‐5p reduced the expression of these RNAs, reduced rRNA levels, and inhibited protein synthesis. In mice, over‐expression of miR‐322 (rodent miR‐424 orthologue) caused fibre atrophy and reduced upstream binding transcription factor expression and rRNA levels. In humans, elevated miR‐424‐5p associated with markers of disease severity in COPD (FEV1%), in patients undergoing aortic surgery (LVEF%), and in patients with ICU‐acquired weakness (days in ICU). In patients undergoing aortic surgery, preoperative miR‐424‐5p expression in skeletal muscle was associated with muscle loss over the following 7 days.ConclusionsThese data suggest that miR‐424‐5p regulates rRNA synthesis by inhibiting Pol I pre‐initiation complex formation. Increased miR‐424‐5p expression in patients with conditions associated with muscle wasting is likely to contribute to the inhibition of protein synthesis and loss of muscle mass.

BackgroundLoss of muscle mass is a co‐morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor‐15 (GDF‐15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF‐15 may contribute to muscle wasting in COPD.MethodsWe determined the expression of GDF‐15 in the serum and muscle of patients with COPD and analysed the association of GDF‐15 expression with muscle mass and exercise performance. To determine whether GDF‐15 had a direct effect on muscle, we also determined the effect of increased GDF‐15 expression on the tibialis anterior of mice by electroporation.ResultsGrowth differentiation factor‐15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF‐15 was inversely correlated with rectus femoris cross‐sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF‐15 levels were associated with 8‐oxo‐dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over‐expression of GDF‐15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF‐15 on muscle mass (P < 0.001).ConclusionsTogether, the data suggest that GDF‐15 contributes to the loss of muscle mass in COPD.

We investigate magnetic properties and statistical effects in 1D strongly repulsive two-component fermions and in a 1D mixture of strongly repulsive polarized fermions and bosons. Universality in the characteristics of phase transitions, magnetization and susceptibility in the presence of an external magnetic field H are analyzed from the exact thermodynamic Bethe ansatz solution. We show explicitly that polarized fermions with a repulsive interaction have antiferromagnetic behavior at zero temperature. A universality class of linear field-dependent magnetization persists for weak and finite strong interaction. The system is fully polarized when the external field exceeds the critical value H F c ≈ 8 γ E F , where E F is the Fermi energy and γ is the dimensionless interaction strength. In contrast, the mixture of polarized fermions and bosons in an external field exhibits square-root field-dependent magnetization in the vicinities of H = 0 and the critical value H =find that a pure boson phase occurs in the absence of the external field, fullypolarized fermions and bosons coexist for 0 < H < H M c , and a fully-polarized fermion phase occurs for H ≥ H M c . This phase diagram for the Bose-Fermi mixture is reminiscent of weakly attractive fermions with population imbalance, where the interacting fermions with opposite spins form singlet pairs. PACS numbers: 03.75.Ss, 05.30.Fk, 71.10.PmThe recent success in experimentally realizing degenerate quantum gases in low dimensions [1,2,3,4,5] has revived interest in one-dimensional (1D) integrable models of interacting fermions and bosons [6,7,8,9,10,11,12,13]. The 1D atomic gases with internal degrees of freedom are tunable interacting many-body systems featuring novel strong correlation effects and subtle quantum phase transitions. Exotic quantum phases in 1D two-component attractive fermions have received considerable interest [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28] due to the experimental observation of fermionic superfluidity and phase transitions [29, 30, 31]. For certain regimes, the twocomponent Fermi gas with population imbalance can be viewed as a strongly interacting Bose-Fermi mixture [32, 33]. However, subtle differences between the bosonic dimer and pure bosons have been observed experimentally [34, 35]. For repulsive interaction, the twocomponent Fermi gas exhibits antiferromagnetic behavior [14, 15, 36, 37, 38, 39]. In contrast to the two-component Fermi gas, the 1D spinor Bose gases [10, 40, 41, 42] possesses novel ferromagnetic properties and collective dynamics of spin waves at temperatures below the degenerate temperature. The subtlety in 1D quantum many-body physics [43] is a result of the dynamical interaction between identical particles and their statistics. On the other hand, the recent success in tuning interspecies Feshbach resonances in Bose-Fermi mixtures of ultracold atoms [34, 35, 44], such as 6 Li+ 7 Li, 6 Li+ 23 Na, 40 K+ 87 Rb, 6 Li+ 87 Rb, opens up a new gateway for exploring many-body physics, including superfluids and Mott insula...

BackgroundLoss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.MethodsThe effect of miR‐422a on SMAD4 expression and transforming growth factor (TGF)‐β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross‐sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).ResultsmiR‐422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR‐422a suppressed SMAD4 expression and inhibited TGF‐beta and bone morphogenetic protein‐dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU‐associated muscle weakness, quadriceps expression of miR‐422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre‐surgery levels of miR‐422a were inversely associated with the amount of muscle that would be lost in the first post‐operative week (r = −0.57, P < 0.001).ConclusionsThese data suggest that differences in miR‐422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF‐beta signalling in skeletal muscle.