DIAPHRAGM MUSCLE STRIP PREPARATION FOR EVALUATION OF GENE THERAPIES IN mdx MICE

1.  Duchenne muscular dystrophy (DMD), a severe muscle wasting disease of young boys with an incidence of one in every 3000, results from a mutation in the gene that encodes dystrophin. The absence of dystrophin expression in skeletal muscles and heart results in the degeneration of muscle fibres and, consequently, severe muscle weakness and wasting. The mdx mouse discovered in 1984, with some adjustments for differences, has proven to be an invaluable model for scientific investigations of dystrophy. 2.  The development of the diaphagm strip preparation provided an ideal experimental model for investigations of skeletal muscle impairments in structure and function induced by interactions of disease- and age-related factors. Unlike the limb muscles of the mdx mouse, which show adaptive changes in structure and function, the diaphragm strip preparation reflects accurately the deterioration in muscle structure and function observed in boys with DMD. 3.  The advent of sophisticated servo motors and force transducers interfaced with state-of-the-art software packages to drive complex experimental designs during the 1990s greatly enhanced the capability of the mdx mouse and the diaphragm strip preparation to evaluate more accurately the impact of the disease on the structure–function relationships throughout the life span of the mouse. 4.  Finally, during the 1990s and through the early years of the 21st century, many promising, sophisticated genetic techniques have been designed to ameliorate the devastating impact of muscular dystrophy on the structure and function of skeletal muscles. During this period of rapid development of promising genetic therapies, the combination of the mdx mouse and the diaphragm strip preparation has provided an ideal model for the evaluation of the success, or failure, of these genetic techniques to improve dystrophic muscle structure, function or both. With the 2 year life span of the mdx mouse, the impact of age-related effects can be studied in this model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72970/1/j.1440-1681.2007.04865.x.pd

Extensive degeneracy, Coulomb phase and magnetic monopoles in an artificial realization of the square ice model

Artificial spin ice systems have been introduced as a possible mean to investigate frustration effects in a well-controlled manner by fabricating lithographically-patterned two-dimensional arrangements of interacting magnetic nanostructures. This approach offers the opportunity to visualize unconventional states of matter, directly in real space, and triggered a wealth of studies at the frontier between nanomagnetism, statistical thermodynamics and condensed matter physics. Despite the strong efforts made these last ten years to provide an artificial realization of the celebrated square ice model, no simple geometry based on arrays of nanomagnets succeeded to capture the macroscopically degenerate ground state manifold of the corresponding model. Instead, in all works reported so far, square lattices of nanomagnets are characterized by a magnetically ordered ground state consisting of local flux-closure configurations with alternating chirality. Here, we show experimentally and theoretically, that all the characteristics of the square ice model can be observed if the artificial square lattice is properly designed. The spin configurations we image after demagnetizing our arrays reveal unambiguous signatures of an algebraic spin liquid state characterized by the presence of pinch points in the associated magnetic structure factor. Local excitations, i.e. classical analogues of magnetic monopoles, are found to be free to evolve in a massively degenerated, divergence-free vacuum. We thus provide the first lab-on-chip platform allowing the investigation of collective phenomena, including Coulomb phases and ice-like physics.Comment: 26 pages, 10 figure

Age- and Gender-Related Changes in Contractile Properties of Non-Atrophied EDL Muscle

Background: In humans, ageing causes skeletal muscles to become atrophied, weak, and easily fatigued. In rodent studies, ageing has been associated with significant muscle atrophy and changes in the contractile properties of the muscles. However, it is not entirely clear whether these changes in contractile properties can occur before there is significant atrophy, and whether males and females are affected differently. Methods and Results: We investigated various contractile properties of whole isolated fast-twitch EDL muscles from adult (2–6 months-old) and aged (12–22 months-old) male and female mice. Atrophy was not present in the aged mice. Compared with adult mice, EDL muscles of aged mice had significantly lower specific force, longer tetanus relaxation times, and lower fatiguability. In the properties of absolute force and muscle relaxation times, females were affected by ageing to a greater extent than males. Additionally, EDL muscles from a separate group of male mice were subjected to eccentric contractions of 15 % strain, and larger force deficits were found in aged than in adult mice. Conclusion: Our findings provide further insight into the muscle atrophy, weakness and fatiguability experienced by the elderly. We have shown that even in the absence of muscle atrophy, there are definite alterations in the physiological properties of whole fast-twitch muscle from ageing mice, and for some of these properties the alterations are mor

The effect of lengthening contractions on neuromuscular junction structure in adult and old mice

Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days following damage. In contrast, in quiescent muscles of old mice, ∼15 % of muscle fibres were denervated and ∼80 % of NMJs showed disruption. This proportion of denervated and partially denervated fibres remained unchanged following recovery from contraction-induced damage in muscles of old mice although ∼25 % of muscle fibres were completely lost by 28 days post-contractions. Thus, in old mice, the failure to restore full muscle force generation that occurs following damage does not appear to be due to any further deficit in the percentage of disrupted NMJs, but appears to be due, at least in part, to the complete loss of muscle fibres following damag

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in α-Dystrobrevin Null Muscle

α-Dystrobrevin is a component of the dystrophin-glycoprotein complex (DGC) and is thought to have both structural and signaling roles in skeletal muscle. Mice deficient for α-dystrobrevin (adbn−/−) exhibit extensive myofiber degeneration and neuromuscular junction abnormalities. However, the biochemical stability of the DGC and the functional performance of adbn−/− muscle have not been characterized. Here we show that the biochemical association between dystrophin and β-dystroglycan is compromised in adbn−/− skeletal muscle, suggesting that α-dystrobrevin plays a structural role in stabilizing the DGC. However, despite muscle cell death and DGC destabilization, costamere organization and physiological performance is normal in adbn−/− skeletal muscle. Our results demonstrate that myofiber degeneration alone does not cause functional deficits and suggests that more complex pathological factors contribute to the development of muscle weakness in muscular dystrophy

Multiparticle azimuthal correlations for extracting event-by-event elliptic and triangular flow in Au + Au collisions at sNN =200 GeV

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1<|η|<3 in Au + Au collisions at sNN=200 GeV, as a function of centrality. The multiparticle cumulant technique is used to obtain the elliptic flow coefficients v2{2},v2{4},v2{6}, and v2{8}, and triangular flow coefficients v3{2} and v3{4}. Using the small-variance limit, we estimate the mean and variance of the event-by-event v2 distribution from v2{2} and v2{4}. In a complementary analysis, we also use a folding procedure to study the distributions of v2 and v3 directly, extracting both the mean and variance. Implications for initial geometrical fluctuations and their translation into the final-state momentum distributions are discussed

Nonperturbative transverse-momentum-dependent effects in dihadron and direct photon-hadron angular correlations in p+p collisions at s =200 GeV

Dihadron and isolated direct photon-hadron angular correlations are measured in p+p collisions at s=200 GeV. The correlations are sensitive to nonperturbative initial-state and final-state transverse momenta kT and jT in the azimuthal nearly back-to-back region Δφ∼π. To have sensitivity to small transverse momentum scales, nonperturbative momentum widths of pout, the out-of-plane transverse-momentum component perpendicular to the trigger particle, are measured. In this region, the evolution of pout can be studied when several different hard scales are measured. These widths are used to investigate possible effects from transverse-momentum-dependent factorization breaking. When accounting for the longitudinal-momentum fraction of the away-side hadron with respect to the near-side trigger particle, the widths are found to increase with the hard scale; this is qualitatively similar to the observed behavior in Drell-Yan and semi-inclusive deep-inelastic scattering interactions, where factorization is predicted to hold. The momentum widths are also studied as a function of center-of-mass energy by comparing to previous measurements at s=510 GeV. The nonperturbative jet widths also appear to increase with s at a similar xT, which is qualitatively consistent to similar measurements in Drell-Yan interactions. Future detailed global comparisons between measurements of processes where transverse-momentum-dependent factorization is predicted to hold and be broken will provide further insight into the role of color in hadronic interactions

Nonperturbative-transverse-momentum broadening in dihadron angular correlations in sNN =200 GeV proton-nucleus collisions

The PHENIX collaboration has measured high-pT dihadron correlations in p+p, p+Al, and p+Au collisions at sNN=200 GeV. The correlations arise from inter- and intrajet correlations and thus have sensitivity to nonperturbative effects in both the initial and final states. The distributions of pout, the transverse-momentum component of the associated hadron perpendicular to the trigger hadron, are sensitive to initial- and final-state transverse momenta. These distributions are measured multidifferentially as a function of xE, the longitudinal momentum fraction of the associated hadron with respect to the trigger hadron. The near-side pout widths, sensitive to fragmentation transverse momentum, show no significant broadening between p+Au, p+Al, and p+p. The away-side nonperturbative pout widths are found to be broadened in p+Au when compared to p+p; however, there is no significant broadening in p+Al compared to p+p collisions. The data also suggest that the away-side pout broadening is a function of Ncoll, the number of binary nucleon-nucleon collisions, in the interaction. The potential implications of these results with regard to initial- and final-state transverse-momentum broadening and energy loss of partons in a nucleus, among other nuclear effects, are discussed