Xanthine oxidase pathway and muscle damage: Insights from McArdle disease

The intent of this review is to summarize current body of knowledge on the potential implication of the xanthine oxidase pathway (XO) on skeletal muscle damage. The possible involvement of the XO pathway in muscle damage is exemplified by the role of XO inhibitors (e.g., allopurinol) in attenuating muscle damage. Reliance on this pathway (as well as on the purine nucleotide cycle) could be exacerbated in conditions of low muscle glycogen availability. Thus, we also summarize current hypotheses on the etiology of both baseline and exertional muscle damage in McArdle disease, a condition caused by inherited deficiency of myophosphorylase. Because myophosphorylase catalyzes the first step of muscle glycogen breakdown, patients are unable to obtain energy from their muscle glycogen stores. Finally, we provide preliminary data from our laboratory on the potential implication of the XO pathway in the muscle damage that is commonly experienced by these patients.

Muscle signaling in exercise intolerance: Insights from the McArdle mouse model

We recently generated a knock-in mouse model (PYGM p.R50X/p.R50X) of McArdle disease (myophosphorylase deficiency). One mechanistic approach to unveil the molecular alterations caused by myophosphorylase deficiency, which is arguably the paradigm of 'exercise intolerance', is to compare the skeletal-muscle tissue of McArdle, heterozygous, and healthy (wild type (wt)) mice. We analyzed in quadriceps muscle of p.R50X/p.R50X (n=4), p.R50X/wt (n=6) and wt/wt mice (n=5) (all male, 8 wk-old) molecular markers of energy-sensing pathways, oxidative phosphorylation (OXPHOS) and autophagy/proteasome systems, oxidative damage and sarcoplamic reticulum (SR) Ca handling. We found a significant group effect for total AMPK (tAMPK) and ratio of phosphorylated (pAMPK)/tAMPK (P=0.012 and 0.033), with higher mean values in p.R50X/p.R50X mice vs. the other two groups. The absence of massive accumulation of ubiquitinated proteins, autophagosomes or lysosomes in p.R50X/p.R50X mice suggested no major alterations in autophagy/proteasome systems. Citrate synthase activity was lower in p.R50X/p.R50X mice vs. the other two groups (P=0.036) but no statistical effect existed for respiratory chain complexes. We found higher levels of 4-hydroxy-2-nonenal-modified proteins in p.R50X/p.R50X and p.R50X/wt mice compared with the wt/wt group (P=0.011). Sarco(endo)plasmic reticulum ATPase 1 (SERCA1) levels detected at 110kDa tended to be higher in p.R50X/p.R50X and p.R50X/wt mice compared with wt/wt animals (P=0.076), but their enzyme activity was normal. We also found an accumulation of phosphorylated SERCA1 in p.R50X/p.R50X animals. Myophosphorylase deficiency causes alterations in sensory energetic pathways together with some evidence of oxidative damage and alterations in Ca handling but with no major alterations in OXPHOS capacity or autophagy/ubiquitination pathways, which suggests that the muscle tissue of patients is likely to adapt overall favorably to exercise training interventions.

Effects of prior heavy exercise on V(over dot)O-2 kinetics during heavy exercise are related to changes in muscle activity

Burnley, M., Doust, J.H., Ball, D. and Jones, A.M. (2002) Effects of prior heavy exercise on VO2 kinetics during heavy exercise are related to changes in muscle activity. Journal of Applied Physiology 93, 167-174. RAE2008

The validity of ultrasound estimation of muscle volumes

Infantolino, B., Gales, D., Winter, S., Challis, J., The validity of ultrasound estimation of muscle volumes, Journal of applied biomechanics, ISSN 1065-8483, Vol. 23, N?. 3, 2007 , pags. 213-217 RAE2008

'Psyching-up' enhances force production during the bench press exercise

Tod, D., Iredale, F., McGuigan, M., Strange, D., Gill, N. (2005). 'Psyching-up' enhances force production during the bench press exercise. Tod, 19 (3), 599-603. RAE2008

'Psyching-up' and muscular force production

Tod, D. A., Iredale, F., Gill, N. (2003). 'Psyching-up' and muscular force production. Sports Medicine, 33 (1), 47-58. RAE2008

In Common Cause: The NATO Multilateral Force and Mixed-Manning Demonstration on USS Claude V. Ricketts, 1964-1965

Priest, A. (2005). In Common Cause: The NATO Multilateral Force and Mixed-Manning Demonstration on USS Claude V. Ricketts, 1964-1965. Journal of Military History, 69 (3), 759-789. RAE2008

The effects of ageing and exercise on skeletal muscle structure and function

Musculoskeletal ageing is associated with profound morphological and functional changes that increase fall risk and disease incidence and is characterised by age-related reductions in motor unit number and atrophy of muscle fibres, particularly type II fibres. Decrements in functional strength and power are relatively modest until the 6th decade, after which the rate of loss exponentially accelerates, particularly beyond the 8th decade of life. Physical activity is a therapeutic modality that can significantly attenuate age-related decline. The underlying signature of ageing, as manifested by perturbed redox homeostasis, leads to a blunting of acute and chronic redox regulated exercise adaptations. Impaired redox regulated exercise adaptations are mechanistically related to altered exercise-induced reactive oxygen and nitrogen species generation and a resultant failure to properly activate redox regulated signaling cascades. Despite the aforementioned specific impairment in redox signaling, exercise induces a plethora of beneficial effects, irrespective of age. There is, therefore, strong evidence for promoting regular physical exercise, especially progressive resistance training as a lifelong habitual practice.

Age- and activity-related differences in the abundance of Myosin essential and regulatory light chains in human muscle

Traditional methods for phenotyping skeletal muscle (e.g., immunohistochemistry) are labor-intensive and ill-suited to multixplex analysis, i.e., assays must be performed in a series. Addressing these concerns represents a largely unmet research need but more comprehensive parallel analysis of myofibrillar proteins could advance knowledge regarding age- and activity-dependent changes in human muscle. We report a label-free, semi-automated and time efficient LC-MS proteomic workflow for phenotyping the myofibrillar proteome. Application of this workflow in old and young as well as trained and untrained human skeletal muscle yielded several novel observations that were subsequently verified by multiple reaction monitoring (MRM).We report novel data demonstrating that human ageing is associated with lesser myosin light chain 1 content and greater myosin light chain 3 content, consistent with an age-related reduction in type II muscle fibers. We also disambiguate conflicting data regarding myosin regulatory light chain, revealing that age-related changes in this protein more closely reflect physical activity status than ageing per se. This finding reinforces the need to control for physical activity levels when investigating the natural process of ageing. Taken together, our data confirm and extend knowledge regarding age- and activity-related phenotypes. In addition, the MRM transitions described here provide a methodological platform that can be fine-tuned to suite multiple research needs and thus advance myofibrillar phenotyping.

The Gospel Worship Service Presents Unique Challenges for Chaplains: A Primer on Leading a Gospel Service in the Air Force

This project examines the challenges military chaplains face when leading Gospel services in the United States Air Force in both domestic and deployed locations. It argues that some chaplains assigned to Gospel services do not have the ministry skills set to lead them effectively. Through quantitative and qualitative research methods involving surveys of 30 military chaplains, lay leaders and parishioners, and follow-up interviews to explore critical issues identified by leaders and congregants alike, this project develops a Gospel service manual. This instructional primer outlines the historical evolution of the Gospel service and addresses its integral elements of worship and challenges that chaplains need to understand to meet the worship needs of multicultural and ecumenical military congregations.

Supplementary Material: PREMATURE EXPRESSION OF AN AGE-ASSOCIATED MUSCLE SENESCENCE PATHWAY IN HIV INFECTION

Supplement online material

A Quantitative Evaluation of the AVITEWRITE Model of Handwriting Learning

Much sensory-motor behavior develops through imitation, as during the learning of handwriting by children. Such complex sequential acts are broken down into distinct motor control synergies, or muscle groups, whose activities overlap in time to generate continuous, curved movements that obey an intense relation between curvature and speed. The Adaptive Vector Integration to Endpoint (AVITEWRITE) model of Grossberg and Paine (2000) proposed how such complex movements may be learned through attentive imitation. The model suggest how frontal, parietal, and motor cortical mechanisms, such as difference vector encoding, under volitional control from the basal ganglia, interact with adaptively-timed, predictive cerebellar learning during movement imitation and predictive performance. Key psycophysical and neural data about learning to make curved movements were simulated, including a decrease in writing time as learning progresses; generation of unimodal, bell-shaped velocity profiles for each movement synergy; size scaling with isochrony, and speed scaling with preservation of the letter shape and the shapes of the velocity profiles; an inverse relation between curvature and tangential velocity; and a Two-Thirds Power Law relation between angular velocity and curvature. However, the model learned from letter trajectories of only one subject, and only qualitative kinematic comparisons were made with previously published human data. The present work describes a quantitative test of AVITEWRITE through direct comparison of a corpus of human handwriting data with the model's performance when it learns by tracing human trajectories. The results show that model performance was variable across subjects, with an average correlation between the model and human data of 89+/-10%. The present data from simulations using the AVITEWRITE model highlight some of its strengths while focusing attention on areas, such as novel shape learning in children, where all models of handwriting and learning of other complex sensory-motor skills would benefit from further research.

Cerebellar Learning in an Opponent Motor Controller for Adaptive Load Compensation and Synergy Formation

This paper shows how a minimal neural network model of the cerebellum may be embedded within a sensory-neuro-muscular control system that mimics known anatomy and physiology. With this embedding, cerebellar learning promotes load compensation while also allowing both coactivation and reciprocal inhibition of sets of antagonist muscles. In particular, we show how synaptic long term depression guided by feedback from muscle stretch receptors can lead to trans-cerebellar gain changes that are load-compensating. It is argued that the same processes help to adaptively discover multi-joint synergies. Simulations of rapid single joint rotations under load illustrates design feasibility and stability.

A Biomechanical Model of Human Oculomotor Plant Kinematics Based Upon Geometric Algebra

A biomechanical model of the human oculomotor plant kinematics in 3-D as a function of muscle length changes is presented. It can represent a range of alternative interpretations of the data as a function of one parameter. The model is free from such deficits as singularities and the nesting of axes found in alternative formulations such as the spherical wrist (Paul, l98l). The equations of motion are defined on a quaternion based representation of eye rotations and are compact atnd computationally efficient.