Miranda D Grounds

University of Western Australia, Perth City, Western Australia, Australia

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Publications (182)645.68 Total impact

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    ABSTRACT: Oxidative stress, caused by excess reactive oxygen species (ROS), has been hypothesised to cause or exacerbate skeletal muscle wasting in a number of diseases and chronic conditions. ROS, such as hydrogen peroxide, have the potential to affect signal transduction pathways such as the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway that regulates protein synthesis. Previous studies have found contradictory outcomes for the effect of ROS on the PI3K/Akt signalling pathway, where oxidative stress can either enhance or inhibit Akt phosphorylation. The apparent contradictions could reflect differences in experimental cell types or types of ROS treatments. We replicate both effects in myotubes of cultured skeletal muscle C2C12 cells, and show that increased oxidative stress can either inhibit or enhance Akt phosphorylation. This differential response could be explained: thiol oxidation of Akt, but not the phosphatases PTEN or PP2A, caused a decline in Akt phosphorylation; whereas the thiol oxidation of Akt, PTEN and PP2A increased Akt phosphorylation. These observations indicate that a more complete understanding of the effects of oxidative stress on a signal transduction pathway comes not only from identifying the proteins susceptible to thiol oxidation, but also their relative sensitivity to ROS. Copyright © 2015. Published by Elsevier Ltd.
    The International Journal of Biochemistry & Cell Biology 02/2015; 62. DOI:10.1016/j.biocel.2015.02.015 · 4.24 Impact Factor
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    ABSTRACT: This study compared the capacity of young and old male C57Bl/6J mice to exercise with increasing resistance over 10 weeks, and its impact on muscle mass. Young mice (aged 15-25 weeks) were subjected to low (LR) and high (HR) resistance exercise, whereas only LR was used for old mice (107-117 weeks). Weekly patterns of voluntary wheel activity, food consumption and body weights were measured. Running patterns changed over time and with age, with two peaks of activity detected for young, but only one for old mice: speed and distance run was also less for old mice. The mass for six limb muscles was measured at the end of the experiment. The most pronounced increase in mass in response to exercise was for the soleus in young and old mice, and also quadriceps and gastrocnemius in young mice. Soleus and quadriceps muscles were analyzed histologically for myofiber number and size. A striking feature was the many small myofibers in response to exercise in young (but not old) soleus, whereas these were not present after exercise in young or old quadriceps. Overall, there was a striking difference in response to exercise between muscles and this was influenced by age. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Scandinavian Journal of Medicine and Science in Sports 02/2015; DOI:10.1111/sms.12416 · 3.17 Impact Factor
  • Nadia Rosenthal, Miranda D Grounds
  • Miranda D Grounds
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    ABSTRACT: A more precise definition of the term 'skeletal muscle regeneration' is required to reduce confusion and misconceptions. In this paper the term is used only for events that follow myofibre necrosis, to result in myogenesis and new muscle formation: other key events include early inflammation and revascularisation, and later fibrosis and re-innervation. The term 'muscle regeneration' is sometimes used casually for situations that do not involve myonecrosis; such as restoration of muscle mass by hypertrophy after atrophy, and other forms of damage to muscle tissue components. These situations are excluded from the definition in this paper which is focussed on mammalian muscles with the long-term aim of clinical translation to enhance new muscle formation after acute or chronic injury or during surgery to replace whole muscles. The paper briefly outlines the cellular events involved in myogenesis during development and post-natal muscle growth, discusses the role of satellite cells in mature normal muscles, and the likely incidence of myofibre necrosis/regeneration in healthy ageing mammals (even when subjected to exercise). The importance of the various components of regeneration is outlined to emphasise that problems in each of these aspects can influence overall new muscle formation; thus care is needed for correct interpretation of altered kinetics. Various markers used to identify regenerating myofibres are critically discussed and, since these can all occur in other conditions, caution is required for accurate interpretation of these cellular events. Finally, clinical situations are outlined where there is a need to enhance skeletal muscle regeneration: these include acute and chronic injuries or transplantation with bioengineering to form new muscles, therapeutic approaches to muscular dystrophies, and comment on proposed stem cell therapies to reduce age-related loss of muscle mass and function.
    The International Journal of Biochemistry & Cell Biology 09/2014; DOI:10.1016/j.biocel.2014.09.010 · 4.24 Impact Factor
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    ABSTRACT: Molecular mechanisms that are associated with age-related denervation and loss of skeletal muscle mass and function (sarcopenia) are described for female C57Bl/6 J mice aged 3, 15, 24, 27 and 29 months (m). Changes in mRNAs and proteins associated with myofibre denervation and protein metabolism in ageing muscles are reported, across the transition from healthy adult myofibres to sarcopenia that occurs between 15-24 m. This onset of sarcopenia at 24 m, corresponded with increased expression of genes associated with neuromuscular junction denervation including Chnrg, Chrnd, Ncam1, Runx1, Gadd45a and Myog. Sarcopenia in quadriceps muscles also coincided with increased protein levels for Igf1 receptor, Akt and ribosomal protein S6 (Rps6) with increased phosphorylation of Rps6 (Ser235/236) and elevated Murf1 mRNA and protein, but not Fbxo32: many of these changes are also linked to denervation. Global transcription profiling via microarray analysis confirmed these functional themes and highlighted additional themes that may be a consequence of pathology associated with sarcopenia, including changes in fatty acid metabolism, extracellular matrix structure and protein catabolism. Ageing was also associated with increased global gene expression variance, consistent with decreased control of gene regulation.
    The International Journal of Biochemistry & Cell Biology 08/2014; 53. DOI:10.1016/j.biocel.2014.04.025 · 4.24 Impact Factor
  • Miranda D Grounds
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    ABSTRACT: Age related loss of skeletal muscle mass and function (sarcopenia) reduces independence and the quality of life for individuals, and leads to falls and fractures with escalating health costs for the rapidly aging human population. Thus there is much interest in developing interventions to reduce sarcopenia. One area that has attracted recent attention is the proposed use of myogenic stem cells to improve regeneration of old muscles. This mini-review challenges the fundamental need for myogenic stem cell therapy for sarcopenia. It presents evidence that demonstrates the excellent capacity of myogenic stem cells from very old rodent and human muscles to form new muscles after experimental myofiber necrosis. The many factors required for successful muscle regeneration are considered with a strong focus on integration of components of old muscle bioarchitecture. The fundamental role of satellite cells in homeostasis of normal aging muscles and the incidence of endogenous regeneration in old muscles is questioned. These issues, combined with problems for clinical myogenic stem cell therapies for severe muscle diseases, raise fundamental concerns about the justification for myogenic stem cell therapy for sarcopenia.
    07/2014; 4(3). DOI:10.4161/bioa.29668
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    ABSTRACT: Sarcopenia is associated with adverse health outcomes. This study investigated whether skeletal muscle gene expression was associated with lean mass and grip strength in community-dwelling older men. Utilising a cross-sectional study design, lean muscle mass and grip strength were measured in 88 men aged 68-76 years. Expression profiles of 44 genes implicated in the cellular regulation of skeletal muscle were determined. Serum was analysed for circulating cytokines TNF (tumour necrosis factor), IL-6 (interleukin 6, IFNG (interferon gamma), IL1R1 (interleukin-1 receptor-1). Relationships between skeletal muscle gene expression, circulating cytokines, lean mass and grip strength were examined. Participant groups with higher and lower values of lean muscle mass (n = 18) and strength (n = 20) were used in the analysis of gene expression fold change. Expression of VDR (vitamin D receptor) [fold change (FC) 0.52, standard error for fold change (SE) ± 0.08, p = 0.01] and IFNG mRNA (FC 0.31; SE ± 0.19, p = 0.01) were lower in those with higher lean mass. Expression of IL-6 (FC 0.43; SE ± 0.13, p = 0.02), TNF (FC 0.52; SE ± 0.10, p = 0.02), IL1R1 (FC 0.63; SE ± 0.09, p = 0.04) and MSTN (myostatin) (FC 0.64; SE ± 0.11, p = 0.04) were lower in those with higher grip strength. No other significant changes were observed. Significant negative correlations between serum IL-6 (R = -0.29, p = 0.005), TNF (R = -0.24, p = 0.017) and grip strength were demonstrated. This novel skeletal muscle gene expression study carried out within a well-characterized epidemiological birth cohort has demonstrated that lower expression of VDR and IFNG is associated with higher lean mass, and lower expression of IL-6, TNF, IL1R1 and myostatin is associated with higher grip strength. These findings are consistent with a role of proinflammatory factors in mediating lower muscle strength in community-dwelling older men.
    Calcified Tissue International 07/2014; 95(4). DOI:10.1007/s00223-014-9894-z · 2.75 Impact Factor
  • Age and Ageing 06/2014; 43(suppl 1):i28-i28. DOI:10.1093/ageing/afu042.6 · 3.11 Impact Factor
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    ABSTRACT: The age-related loss of skeletal muscle mass and function is termed sarcopenia and has been attributed to a decline in concentrations of insulin-like growth factor-1 (IGF-1). We hypothesized that constitutively expressed IGF-1 within skeletal muscles with or without exercise would prevent sarcopenia. Male transgenic mice that overexpress IGF-1 Ea in skeletal muscles were compared with wild-type littermates. Four-month-old mice were assigned to be sedentary, or had access to free-running wheels, until 18 or 28 months of age. In wild-type mice, the mass of the quadriceps muscles was reduced at 28 months and exercise prevented such loss, without affecting the diameter of myofibers. Conversely, increased IGF-1 alone was ineffective, whereas the combination of exercise and IGF-1 was additive in maintaining the diameter of myofibers in the quadriceps muscles. For other muscles, the combination of IGF-1 and exercise was variable and either increased or decreased the mass at 18 months of age, but was ineffective thereafter. Despite an increase in the diameter of myofibers, grip strength was not improved. In conclusion, our data show that exercise and IGF-1 have a modest effect on reducing aged-related wasting of skeletal muscle, but that there is no improvement in muscle function when assessed by grip strength.
    Scandinavian Journal of Medicine and Science in Sports 04/2014; 24(6). DOI:10.1111/sms.12200 · 3.17 Impact Factor
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    ABSTRACT: We present the assessment of ex vivo mouse muscle tissue by quantitative parametric imaging of the near-infrared attenuation coefficient µt using optical coherence tomography. The resulting values of the local total attenuation coefficient µt (mean ± standard error) from necrotic lesions in the dystrophic skeletal muscle tissue of mdx mice are higher (9.6 ± 0.3 mm(-1)) than regions from the same tissue containing only necrotic myofibers (7.0 ± 0.6 mm(-1)), and significantly higher than values from intact myofibers, whether from an adjacent region of the same sample (4.8 ± 0.3 mm(-1)) or from healthy tissue of the wild-type C57 mouse (3.9 ± 0.2 mm(-1)) used as a control. Our results suggest that the attenuation coefficient could be used as a quantitative means to identify necrotic lesions and assess skeletal muscle tissue in mouse models of human Duchenne muscular dystrophy.
    Biomedical Optics Express 04/2014; 5(4):1217-32. DOI:10.1364/BOE.5.001217 · 3.50 Impact Factor
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    ABSTRACT: Dysferlin is a membrane associated protein involved in vesicle trafficking and fusion. Defects in dysferlin result in limb-girdle muscular dystrophy type 2B and Miyoshi myopathy in humans and myopathy in A/J(dys-/-) and BLAJ mice, but the pathomechanism of the myopathy is not understood. Oil Red O staining showed many lipid droplets within the psoas and quadriceps muscles of dysferlin-deficient A/J(dys-/-) mice aged 8 and 12 months, and lipid droplets were also conspicuous within human myofibers from patients with dysferlinopathy (but not other myopathies). Electron microscopy of 8-month-old A/J(dys-/-) psoas muscles confirmed lipid droplets within myofibers and showed disturbed architecture of myofibers. In addition, the presence of many adipocytes was confirmed, and a possible role for dysferlin in adipocytes is suggested. Increased expression of mRNA for a gene involved in early lipogenesis, CCAAT/enhancer binding protein-δ, in 3-month-old A/J(dys-/-) quadriceps (before marked histopathology is evident), indicates early induction of lipogenesis/adipogenesis within dysferlin-deficient muscles. Similar results were seen for dysferlin-deficient BLAJ mice. These novel observations of conspicuous intermyofibrillar lipid and progressive adipocyte replacement in dysferlin-deficient muscles present a new focus for investigating the mechanisms that result in the progressive decline of muscle function in dysferlinopathies.
    American Journal Of Pathology 03/2014; DOI:10.1016/j.ajpath.2014.02.005 · 4.60 Impact Factor
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    ABSTRACT: The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles.
    PLoS ONE 02/2014; 9(2):e89277. DOI:10.1371/journal.pone.0089277 · 3.53 Impact Factor
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    Mamta Rai, Upendra Nongthomba, Miranda D Grounds
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    ABSTRACT: Many aspects of skeletal muscle biology are remarkably similar between mammals and tiny insects, and experimental models of mice and flies (Drosophila) provide powerful tools to understand factors controlling the growth, maintenance, degeneration (atrophy and necrosis), and regeneration of normal and diseased muscles, with potential applications to the human condition. This review compares the limb muscles of mice and the indirect flight muscles of flies, with respect to the mechanisms of adult myofiber formation, homeostasis, atrophy, hypertrophy, and the response to muscle degeneration, with some comment on myogenic precursor cells and common gene regulatory pathways. There is a striking similarity between the species for events related to muscle atrophy and hypertrophy, without contribution of any myoblast fusion. Since the flight muscles of adult flies lack a population of reserve myogenic cells (equivalent to satellite cells), this indicates that such cells are not required for maintenance of normal muscle function. However, since satellite cells are essential in postnatal mammals for myogenesis and regeneration in response to myofiber necrosis, the extent to which such regeneration might be possible in flight muscles of adult flies remains unclear. Common cellular and molecular pathways for both species are outlined related to neuromuscular disorders and to age-related loss of skeletal muscle mass and function (sarcopenia). The commonality of events related to skeletal muscles in these disparate species (with vast differences in size, growth duration, longevity, and muscle activities) emphasizes the combined value and power of these experimental animal models.
    Current Topics in Developmental Biology 01/2014; 108:247-81. DOI:10.1016/B978-0-12-391498-9.00007-3 · 4.21 Impact Factor
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    ABSTRACT: We have developed an extremely miniaturized optical coherence tomography (OCT) needle probe (outer diameter 310 µm) with high sensitivity (108 dB) to enable minimally invasive imaging of cellular structure deep within skeletal muscle. Three-dimensional volumetric images were acquired from ex vivo mouse tissue, examining both healthy and pathological dystrophic muscle. Individual myofibers were visualized as striations in the images. Degradation of cellular structure in necrotic regions was seen as a loss of these striations. Tendon and connective tissue were also visualized. The observed structures were validated against co-registered hematoxylin and eosin (H&E) histology sections. These images of internal cellular structure of skeletal muscle acquired with an OCT needle probe demonstrate the potential of this technique to visualize structure at the microscopic level deep in biological tissue in situ.
    Biomedical Optics Express 12/2013; 5(1):136-48. DOI:10.1364/BOE.5.000136 · 3.50 Impact Factor
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    ABSTRACT: Oxidative stress caused by reactive oxygen species is proposed to cause age related muscle wasting (sarcopenia). Reversible oxidation of protein thiols by reactive oxygen species can affect protein function, so we evaluated whether muscle wasting in normal aging was associated with a pervasive increase in reversible oxidation of protein thiols or with an increase in irreversible oxidative damage to macromolecules. In gastrocnemius muscles of C57BL/6J female mice aged 3, 15, 24, 27, and 29 months there was no age related increase in protein thiol oxidation. In contrast, there was a significant correlation (R (2) = 0.698) between increasing protein carbonylation, a measure of irreversible oxidative damage to proteins, and loss of mass of gastrocnemius muscles in aging female mice. In addition, there was an age-related increase in lipofuscin content, an aggregate of oxidised proteins and lipids, in quadriceps limb muscles in aging female mice. However, there was no evidence of an age-related increase in malondialdehyde or F2-isoprostanes levels, which are measures of oxidative damage to lipids, in gastrocnemius muscles. In summary, this study does not support the hypothesis that a pervasive increase in protein thiol oxidation is a contributing factor to sarcopenia. Instead, the data are consistent with an aging theory which proposes that molecular damage to macromolecules leads to the structural and functional disorders associated with aging.
    Biogerontology 12/2013; DOI:10.1007/s10522-013-9483-y · 3.01 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) are not only a cause of oxidative stress in a range of disease conditions but are also important regulators of physiological pathways in vivo. One mechanism whereby ROS can regulate cell function is by modification of proteins through the reversible oxidation of their thiol groups. An experimental challenge has been the relative lack of techniques to probe the biological significance of protein thiol oxidation in complex multicellular tissues and organs. We have developed a sensitive and quantitative fluorescent labelling technique to detect and localise protein thiol oxidation in histological tissue sections. In our technique, reduced and oxidised protein thiols are visualised and quantified on two consecutive tissue sections and the extent of protein thiol oxidation is expressed as a percentage of total protein thiols (reduced plus oxidised). We tested the application of this new technique using muscles of dystrophic (mdx) and wild-type C57Bl/10Scsn (C57) mice. In mdx myofibres, protein thiols were consistently more oxidised (19 ±3%) compared with healthy myofibres (10±1%) in C57 mice. A striking observation was the localisation of intensive protein thiol oxidation (70±9%) within myofibres associated with necrotic damage. Oxidative stress is an area of active investigation in many fields of research, and this technique provides a useful tool for locating and further understanding protein thiol oxidation in normal, damaged and diseased tissues.
    Free Radical Biology and Medicine 10/2013; 65. DOI:10.1016/j.freeradbiomed.2013.09.024 · 5.71 Impact Factor
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    ABSTRACT: The overexpression of NF-κB signaling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-κB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne Muscular Dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density, and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in-vitro NF-κB inhibitory activity of Compound A in H-2K(b) -tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated Cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels, and reduced IL-6, CCL2, IFN-γ, TNF, and IL-12p70 cytokine levels in gastrocnemii muscles. Compared with Compound A, treatment with prednisolone - a classical glucocorticoid - in both wild-type and mdx mice was associated with reduced body weight, reduced gastrocnemii, tibialis anterior, and extensor digitorum longus muscle mass, and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the gastrocnemii muscles of mdx mice, and had less favorable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn, Igf1 in gastrocnemii muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective glucocorticoid receptor modulation by Compound A represents a potential therapeutic strategy to improve dystrophic pathology.
    The Journal of Pathology 10/2013; 231(2). DOI:10.1002/path.4231 · 7.33 Impact Factor
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    ABSTRACT: Minimally invasive, high-resolution imaging of muscle necrosis has the potential to aid in the assessment of diseases such as Duchenne muscular dystrophy. Undamaged muscle tissue possesses high levels of optical birefringence due to its anisotropic ultrastructure, and this birefringence decreases when the tissue undergoes necrosis. In this study, we present a novel technique to image muscle necrosis using polarization-sensitive optical coherence tomography (PS-OCT). From PS-OCT scans, our technique is able to quantify the birefringence in muscle tissue, generating an image indicative of the tissue ultrastructure, with areas of abnormally low birefringence indicating necrosis. The technique is demonstrated on excised skeletal muscles from exercised dystrophic mdx mice, and control C57BL/10ScSn mice, with the resulting images validated against co-located histological sections. The technique additionally gives a measure of the proportion (volume fraction) of necrotic tissue within the three-dimensional imaging field of view. The percentage necrosis assessed by this technique is compared against the percentage necrosis obtained from manual assessment of histological sections, and the difference between the two methods is found to be comparable to the inter-observer variability of the histological assessment. This is the first published demonstration of PS-OCT to provide automated assessment of muscle necrosis.
    Journal of Applied Physiology 08/2013; 115(9). DOI:10.1152/japplphysiol.00265.2013 · 3.43 Impact Factor
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    ABSTRACT: Oxidative stress has been implicated in the pathology of the lethal skeletal muscle disease Duchenne Muscular Dystrophy (DMD), and various antioxidants have been investigated as a potential therapy. Recently, treatment of the mdx mouse model for DMD with the antioxidant and cysteine and glutathione (GSH) precursor n-acetylcysteine (NAC) was shown to decrease protein thiol oxidation and improve muscle pathology and ex vivo muscle strength. This study further investigates the mechanism for the benefits of NAC on dystrophic muscle by administering L-2-Oxothiazolidine-4-Carboxylate (OTC) which also upregulates intracellular cysteine and GSH, but does not directly function as an antioxidant. We observed that OTC, like NAC, decreases protein thiol oxidation, decreases pathology and increases strength, suggesting that the both NAC and OTC function via increasing cysteine and GSH content of dystrophic muscle. We demonstrate that mdx muscle is not deficient in either cysteine or GSH and that these are not increased by OTC treatment. However, we show that dystrophic muscle of 12 week old mdx mice is deficient in taurine, a by-product of disposal of excess cysteine, a deficiency that is ameliorated by OTC treatment. These data suggest that in dystrophic muscles, apart from the strong association of increased oxidative stress and protein thiol oxidation with dystropathology, another major issue is an insufficiency in taurine that can be corrected by increasing the availability of cysteine. This study provides new insight into the molecular mechanism underlying the benefits of NAC in muscular dystrophy and supports the use of OTC as an alternative drug for potential clinical applications to DMD.
    The international journal of biochemistry & cell biology 07/2013; DOI:10.1016/j.biocel.2013.07.009 · 4.24 Impact Factor
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    ABSTRACT: Circadian rhythms and metabolism are tightly integrated and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 hours (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21 and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 hours. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors, MyoD and myogenin, during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of Murf1, Akt1 and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of AKT(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both AKT and S6 in muscles, indicative of inactivation. Hepatic phosphorylated AKT(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic AKT(473) phosphorylation compared with fed levels, although (unlike in muscle) did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signalling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation.
    AJP Cell Physiology 04/2013; 305(1). DOI:10.1152/ajpcell.00027.2013 · 3.67 Impact Factor

Publication Stats

6k Citations
645.68 Total Impact Points


  • 1982–2015
    • University of Western Australia
      • • School of Anatomy, Physiology and Human Biology
      • • School of Pathology and Laboratory Medicine
      Perth City, Western Australia, Australia
  • 2011
    • Baylor College of Medicine
      • Department of Pediatrics
      Houston, Texas, United States
  • 2007
    • University of Oxford
      • MRC Functional Genomics Unit
      Oxford, ENG, United Kingdom
  • 1993–1995
    • University of Manitoba
      Winnipeg, Manitoba, Canada
  • 1986–1987
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
  • 1980–1983
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 1981
    • Royal Perth Hospital
      Perth City, Western Australia, Australia