Regulation of Skeletal Muscle Plasticity by the Gut Microbiome

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight and mean and fiber-type specific cross-sectional area (CSA). The plantaris muscle of mice who ran with antibiotic-induced dysbiosis showed a blunted glycolytic to oxidative fiber-type shift, decreased myonuclear accretion and satellite cell abundance compared to non-treated runners. These results are the first to demonstrate that an intact microbiome is necessary for skeletal muscle adaption to exercise. I next tested if the gut microbiome mitigates skeletal muscle atrophy induced by hind limb immobilization. Eighteen, four-month old, female C57Bl/6J mice were divided into two groups (n=9/group), that received cecal microbial transfers from either exercise-trained or sedentary donors. After four weeks of cecal transplants, the recipient mice underwent 10-days of single leg hind-limb immobilization. Immunohistochemistry analysis revealed that the recipients of the exercise-trained donors experienced significantly less skeletal muscle atrophy of the soleus muscle, as measures by mean fiber and fiber-type specific CSA. The transfer of microbiome from exercise-trained donors also led to a preservation of Type-2A fibers in the immobilized soleus muscle. These results demonstrated that the transfer of a microbiome from an exercise-trained host into recipients mitigated skeletal muscle atrophy, in addition to the persevering Type-2A fibers abundance during atrophy To better understand how the gut microbiome acts to modulate skeletal muscle mass and fiber-type composition, metagenomic sequencing was performed on donor and recipient of exercise-trained and sedentary cecal content. Sequencing data revealed significant differences in the microbiome between the two recipient groups. Further microbial functional comparisons were made and distinguished significant associations in fucose degradation and histidine metabolism in the recipients who received microbiome from exercised-trained donors. To further interrogate the metagenomic sequencing, microbial sequence features were analyzed with MelonnPan to determine predictive metabolites associated with each recipient group. Lipids and bile acids metabolites were significantly associated with the recipients of the exercise-trained donors. There was a trend for imidazole propionate to be associated with the recipients of the exercise-trained donors. The metagenomic analysis indicated the microbiome from an exercise-trained host was associated with metabolic pathways that generate short chain fatty acids (fucose degradation) and the histidine-derived metabolite imidazole propionate. The results from this dissertation provide evidence of crosstalk between skeletal muscle and the gut microbiome, providing for the first-time data that demonstrates the gut microbiome influences both anabolic and catabolic signaling in skeletal muscle. Although a direct mechanism for the skeletal muscle-gut microbiome interaction was not found, the metabolites propionate and imidazole propionate were identified as possible candidate for future studies. A general conclusion from the two studies described in this dissertation provides new evidence for the regulation of skeletal muscle mass and fiber-type composition. Future work will need to focus on the identification of the gut microbial-derived metabolites promote anabolic pathways in skeletal muscle. Additional studies should also determine if the attenuation in atrophy induced by hind limb immobilization is conserved in other models of atrophy as observed with skeletal muscle wasting diseases and space exploration

Effects of exercise-based cardiac rehabilitation on cardiorespiratory fitness: A meta-analysis of UK studies

Background Exercise-based cardiac rehabilitation can promote meaningful improvements in cardiorespiratory fitness (fitness) but the magnitude of such improvements varies according to local characteristics of exercise programmes. We aimed to determine if cardiac rehabilitation (CR), as practised in the United Kingdom (UK), could promote meaningful changes in fitness and to identify programme characteristics which may moderate these changes. Methods Electronic and manual searches to identify UK CR studies reporting fitness at baseline and follow up. Change in fitness (Δfitness) was expressed as mean difference (95% CI) and effect size (ES). A random effects model was used to calculate the mean estimate for change in Δfitness. Between-group heterogeneity was quantified (Q) and investigated using planned sub-group analyses. Results We identified n = 11 studies containing 16 patient groups (n = 1 578) which used the incremental shuttle walking test (ISWT) (distance walked) to assess fitness. The overall mean estimate for Δfitness showed a significant increase in distance walked (ES = 0.48, P  12 exercise sessions compared with those receiving n ≤ 12 sessions. Conclusion We found significant increases in fitness (based on ISWT) in patients attending exercise-based CR in the UK. However, UK studies provide approximately one-third of the exercise “dose”, and produce gains in fitness less than half the magnitude reported in international studies

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model