Australian Institute of Musculoskeletal Science

St Albans, Australia

Australian Institute of Musculoskeletal Science

St Albans, Australia
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McQuade R.M.,Victoria University of Melbourne | Stojanovska V.,Victoria University of Melbourne | Donald E.L.,Victoria University of Melbourne | Rahman A.A.,Victoria University of Melbourne | And 7 more authors.
Frontiers in Physiology | Year: 2017

Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI), commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg-1) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post-treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea. © 2017 McQuade, Stojanovska, Donald, Rahman, Campelj, Abalo, Rybalka, Bornstein and Nurgali.

Stojanovska V.,University of Western Australia | McQuade R.,University of Western Australia | Rybalka E.,University of Western Australia | Rybalka E.,Victoria University of Melbourne | And 2 more authors.
Current Medicinal Chemistry | Year: 2017

Platinum-based anti-cancer agents, which include cisplatin, carboplatin and oxaliplatin, are an important class of drugs used in clinical setting to treat a variety of cancers. The cytotoxic efficacy of these drugs is mediated by the formation of inter-strand and intrastrand crosslinks, or platinum adducts on nuclear DNA. There is also evidence demonstrating that mitochondrial DNA is susceptible to platinum-adduct damage in dorsal root ganglia neurons. Although all platinum-based agents form similar DNA adducts, they are quite different in terms of activation, systemic toxicity and tolerance. Platinum-based agents are well known for their neurotoxicity and gastrointestinal side-effects which are major causes for dose limitation and treatment discontinuation compromising the efficacy of anti-cancer treatment. Accumulating evidence in non-neuronal cells shows that the copper transport system is associated with platinum drug sensitivity and resistance. There is minimal research concerning the role of copper transporters within the central and peripheral nervous systems. It is unclear whether neurons are more sensitive to platinum-based drugs, are insufficient in drug clearance, or whether platinum accumulation affects intracellular copper status and coppermediated functions. Understanding these mechanisms is important as neurotoxicity is the predominant side-effect of platinum-based chemotherapy. This review highlights the role of copper transporters in drug influx, differences in drug activation and side-effects caused by platinum-based agents, as well as their association with central and peripheral neuropathies and gastrointestinal toxicities. © 2017 Bentham Science Publishers.

Rybalka E.,Victoria University of Melbourne | Rybalka E.,Australian Institute of Musculoskeletal Science | Timpani C.A.,Victoria University of Melbourne | Cooke M.B.,Victoria University of Melbourne | And 4 more authors.
PLoS ONE | Year: 2014

Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrientderivative substrate combination fed into the Kreb's cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle. © 2014 Rybalka et al.

Rybalka E.,Victoria University of Melbourne | Rybalka E.,Australian Institute of Musculoskeletal Science | Timpani C.A.,Victoria University of Melbourne | Stathis C.G.,Victoria University of Melbourne | And 5 more authors.
Nutrients | Year: 2015

Duchenne Muscular Dystrophy (DMD) is a fatal genetic muscle wasting disease with no current cure. A prominent, yet poorly treated feature of dystrophic muscle is the dysregulation of energy homeostasis which may be associated with intrinsic defects in key energy systems and promote muscle wasting. As such, supplementative nutriceuticals that target and augment the bioenergetical expansion of the metabolic pathways involved in cellular energy production have been widely investigated for their therapeutic efficacy in the treatment of DMD. We describe the metabolic nuances of dystrophin-deficient skeletal muscle and review the potential of various metabogenic and nutriceutical compounds to ameliorate the pathological and clinical progression of the disease. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Sorensen J.C.,Victoria University of Melbourne | Sorensen J.C.,Australian Institute of Musculoskeletal Science | Cheregi B.D.,Victoria University of Melbourne | Timpani C.A.,Victoria University of Melbourne | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2016

Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions. © 2016 Springer-Verlag Berlin Heidelberg

Scott D.,University of Melbourne | Scott D.,Australian Institute of Musculoskeletal Science | Sanders K.M.,University of Melbourne | Sanders K.M.,Australian Institute of Musculoskeletal Science | And 6 more authors.
Obesity | Year: 2014

Objectives To determine whether obesity concurrent with sarcopenia (low muscle mass) or dynapenia (low muscle strength) is associated with increased falls risk in middle-aged and older adults. Methods 5-year prospective cohort study including 674 community-dwelling volunteers (mean±SD age 61.4±7.0 years; 48% female). Sarcopenia and dynapenia were defined as lowest sex-specific tertiles for dual-energy X-ray (DXA)-assessed appendicular lean mass (adjusted for height and fat mass) or lower-limb strength, respectively. Obesity was defined as the highest tertiles of DXA-assessed total or trunk fat mass. Change in falls risk was calculated using the Physiological Profile Assessment (z-scores: 0-1=mild increased risk; 1-2=moderate increased risk; >2=marked increased risk). Results Multivariable linear regression analyses revealed mild but significantly increased falls risk scores for dynapenic obesity (change in mean z-score compared to non-dynapenic, non-obese group: 0.33, 95% CI 0.06-0.59 [men] and 0.46, 95% CI 0.21-0.72 [women]) and dynapenia (0.25, 95% CI 0.05-0.46 [women only]). Conclusions Dynapenic obesity, but not sarcopenic obesity, is predictive of increased falls risk score in middle-aged and older adults.s In clinical settings, muscle function assessments may be useful for predicting falls risk in obese patients. Copyright © 2014 The Obesity Society.

Timpani C.A.,Victoria University of Melbourne | Hayes A.,Victoria University of Melbourne | Hayes A.,Australian Institute of Musculoskeletal Science | Rybalka E.,Victoria University of Melbourne | Rybalka E.,Australian Institute of Musculoskeletal Science
Medical Hypotheses | Year: 2015

Duchenne Muscular Dystrophy (DMD) is a fatal neuromuscular disease that is characterised by dystrophin-deficiency and chronic Ca2+-induced skeletal muscle wasting, which currently has no cure. DMD was once considered predominantly as a metabolic disease due to the myriad of metabolic insufficiencies evident in the musculature, however this aspect of the disease has been extensively ignored since the discovery of dystrophin. The collective historical and contemporary literature documenting these metabolic nuances has culminated in a series of studies that importantly demonstrate that metabolic dysfunction exists independent of dystrophin expression and a mild disease phenotype can be expressed even in the complete absence of dystrophin expression. Targeting and supporting metabolic pathways with anaplerotic and other energy-enhancing supplements has also shown therapeutic value. We explore the hypothesis that DMD is characterised by a systemic mitochondrial impairment that is central to disease aetiology rather than a secondary pathophysiological consequence of dystrophin-deficiency. © 2015 The Authors.

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