ORCID Profile
0000-0003-1993-4367
Current Organisations
Deakin University - Geelong Campus at Waurn Ponds
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Monash University
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Deakin University
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Publisher: American Physiological Society
Date: 07-2005
DOI: 10.1152/AJPREGU.00378.2004
Abstract: We investigated whether depressed muscle Na + -K + -ATPase activity with exercise reflected a loss of Na + -K + -ATPase units, the time course of its recovery postexercise, and whether this depressed activity was related to increased Na + -K + -ATPase isoform gene expression. Fifteen subjects performed fatiguing, knee extensor exercise at ∼40% maximal work output per contraction. A vastus lateralis muscle biopsy was taken at rest, fatigue, 3 h, and 24 h postexercise and analyzed for maximal Na + -K + -ATPase activity via 3- O-methylfluorescein phosphatase (3- O-MFPase) activity, Na + -K + -ATPase content via [ 3 H]ouabain binding sites, and Na + -K + -ATPase α 1 -, α 2 -, α 3 -, β 1 -, β 2 - and β 3 -isoform mRNA expression by real-time RT-PCR. Exercise [352 (SD 267) s] did not affect [ 3 H]ouabain binding sites but decreased 3- O-MFPase activity by 10.7 (SD 8)% ( P 0.05), which had recovered by 3 h postexercise, without further change at 24 h. Exercise elevated α 1 -isoform mRNA by 1.5-fold at fatigue ( P 0.05). This increase was inversely correlated with the percent change in 3- O-MFPase activity from rest to fatigue (%Δ3- O-MFPase rest-fatigue ) ( r = −0.60, P 0.05). The average postexercise (fatigue, 3 h, 24 h) α 1 -isoform mRNA was increased 1.4-fold ( P 0.05) and approached a significant inverse correlation with %Δ3- O-MFPase rest-fatigue ( r = −0.56, P = 0.08). Exercise elevated α 2 -isoform mRNA at fatigue 2.5-fold ( P 0.05), which was inversely correlated with %Δ3- O-MFPase rest-fatigue ( r = −0.60, P = 0.05). The average postexercise α 2 -isoform mRNA was increased 2.2-fold ( P 0.05) and was inversely correlated with the %Δ3- O-MFPase rest-fatigue ( r = −0.68, P 0.05). Nonsignificant correlations were found between %Δ3- O-MFPase rest-fatigue and other isoforms. Thus acute exercise transiently decreased Na + -K + -ATPase activity, which was correlated with increased Na + -K + -ATPase gene expression. This suggests a possible signal-transduction role for depressed muscle Na + -K + -ATPase activity with exercise.
Publisher: American Society for Clinical Investigation
Date: 20-09-2018
Publisher: American Physiological Society
Date: 05-2004
DOI: 10.1152/AJPENDO.00462.2003
Abstract: The AMP-activated protein kinase (AMPK) cascade has been linked to many of the acute effects of exercise on skeletal muscle substrate metabolism, as well as to some of the chronic training-induced adaptations. We determined the effect of 3 wk of intensified training (HIT 7 sessions of 8 × 5 min at 85% V̇o 2 peak ) in skeletal muscle from well-trained athletes on AMPK responsiveness to exercise. Rates of whole body substrate oxidation were determined during a 90-min steady-state ride (SS) pre- and post-HIT. Muscle metabolites and AMPK signaling were determined from biopsies taken at rest and immediately after exercise during the first and seventh HIT sessions, performed at the same (absolute) pre-HIT work rate. HIT decreased rates of whole body carbohydrate oxidation ( P 0.05) and increased rates of fat oxidation ( P 0.05) during SS. Resting muscle glycogen and its utilization during intense exercise were unaffected by HIT. However, HIT induced a twofold decrease in muscle [lactate] ( P 0.05) and resulted in tighter metabolic regulation, i.e., attenuation of the decrease in the PCr/(PCr + Cr) ratio and of the increase in [AMP free ]/ATP. Resting activities of AMPKα1 and -α2 were similar post-HIT, with the magnitude of the rise in response to exercise similar pre- and post-HIT. AMPK phosphorylation at Thr 172 on both the α1 and α2 subunits increased in response to exercise, with the magnitude of this rise being similar post-HIT. Acetyl-coenzyme A carboxylase-β phosphorylation was similar at rest and, despite HIT-induced increases in whole body rates of fat oxidation, did not increase post-HIT. Our results indicate that, in well-trained in iduals, short-term HIT improves metabolic control but does not blunt AMPK signaling in response to intense exercise.
Publisher: American Physiological Society
Date: 10-2004
DOI: 10.1152/JAPPLPHYSIOL.00371.2004
Abstract: The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (V̇o 2 peak ) and then to fatigue at 92% V̇o 2 peak . NAC was intravenously infused at 125 mg·kg −1 ·h −1 for 15 min and then at 25 mg·kg −1 ·h −1 for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% V̇o 2 peak was reproducible in preliminary trials (coefficient of variation 5.6 ± 0.6%) and with NAC was enhanced by 26.3 ± 9.1% (NAC 6.4 ± 0.6 min vs. Con 5.3 ± 0.7 min P 0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue ( P 0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC ( P 0.001). Muscle TGSH ( P 0.05) declined and muscle GSH tended to decline ( P = 0.06) during exercise. Both were greater with NAC ( P 0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise ( P 0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained in iduals, with enhanced muscle cysteine and GSH availability a likely mechanism.
Publisher: Wiley
Date: 19-01-2007
DOI: 10.1111/J.1748-1716.2006.01635.X
Abstract: This study investigated the effects of endurance training status and sex differences on skeletal muscle Na+,K+-pump mRNA expression, content and activity. Forty-five endurance-trained males (ETM), 11 recreationally active males (RAM), and nine recreationally active females (RAF) underwent a vastus lateralis muscle biopsy. Muscle was analysed for Na+,K+-pump alpha1, alpha2, alpha3, beta1, beta2 and beta3 isoform mRNA expression (real-time reverse transcription-polymerase chain reaction), content ([3H]-ouabain-binding site) and maximal activity (3-O-methylfluorescein phosphatase, 3-O-MFPase). ETM demonstrated lower alpha1, alpha3, beta2 and beta3 mRNA expression by 74%, 62%, 70% and 82%, respectively, than RAM (P<0.04). In contrast, [3H]-ouabain binding and 3-O-MFPase activity were each higher in ETM than in RAM, by 16% (P<0.03). RAM demonstrated a 230% and 364% higher alpha3 and beta3 mRNA expression than RAF, respectively (P<0.05), but no significant sex differences were found for alpha1, alpha2, beta1 or beta2 mRNA, [3H]-ouabain binding or 3-O-MFPase activity. No significant correlation was found between years of endurance training and either [3H]-ouabain binding or 3-O-MFPase activity. Significant but weak correlations were found between the number of training hours per week and 3-O-MFPase activity (r=0.31, P<0.02) and between incremental exercise VO2(peak)) and both [3H]-ouabain binding (r=0.33, P<0.01) and 3-O-MFPase activity (r=0.28, P<0.03). Isoform-specific differences in Na+,K+-pump mRNA expression were found with both training status and sex differences, but only training status influenced Na+,K+-pump content and maximal activity in human skeletal muscle.
Publisher: Informa UK Limited
Date: 27-10-2009
DOI: 10.1517/14728210903369351
Abstract: Cancer cachexia is a complex syndrome that describes the progressive muscle wasting and weakness in many cancer patients. Muscle wasting reduces the ability of affected patients to perform the tasks of daily living and causes severe fatigue, leading to a reduction in quality of life. Cancer cachexia reduces patient response to anti-neoplastic treatments, increases the risk of postoperative complications and accounts for > 20% of cancer-related deaths. The pathogenesis of cancer cachexia is multifactorial and includes anorexia, inflammation, metabolic disturbances and enhanced muscle proteolysis, and each of these presents as a potential therapeutic target for ameliorating cancer cachexia. This review provides an update on some of the emerging drugs for cancer cachexia. This is a review of the current status of emerging therapies for cancer cachexia. An increasing number of studies are focused on the development of novel therapies for cancer cachexia. Initial studies concentrated on the treatment of anorexia, but now aim to attenuate inflammation or muscle proteolysis, or to use different drugs in combination so as to treat several aspects of cachexia simultaneously. There are several existing and emerging drugs with the potential to ameliorate cancer cachexia, but the most efficacious treatment will probably come from combined drug therapies.
Publisher: American Physiological Society
Date: 02-2006
DOI: 10.1152/AJPREGU.00172.2005
Abstract: This study investigated effects of prolonged submaximal exercise on Na + -K + -ATPase mRNA and protein expression, maximal activity, and content in human skeletal muscle. We also investigated the effects on mRNA expression of the transcription initiator gene, RNA polymerase II (RNAP II), and key genes involved in protein translation, eukaryotic initiation factor-4E (eIF-4E) and 4E-binding protein 1 (4E-BP1). Eleven subjects (6 men, 5 women) cycled at 75.5% (SD 4.8%) peak O 2 uptake and continued until fatigue. A vastus lateralis muscle biopsy was taken at rest, fatigue, and 3 and 24 h postexercise. We analyzed muscle for Na + -K + -ATPase α 1 , α 2 , α 3 , β 1 , β 2 , and β 3 , as well for RNAP II, eIF-4E, and 4E-BP1 mRNA expression by real-time RT-PCR and Na + -K + -ATPase isoform protein abundance using immunoblotting. Muscle homogenate maximal Na + -K + -ATPase activity was determined by 3 -O-methylfluorescein phosphatase activity and Na + -K + -ATPase content by [ 3 H]ouabain binding. Cycling to fatigue [54.5 (SD 20.6) min] immediately increased α 3 ( P = 0.044) and β 2 mRNA ( P = 0.042) by 2.2- and 1.9-fold, respectively, whereas α 1 mRNA was elevated by 2.0-fold at 24 h postexercise ( P = 0.036). A significant time main effect was found for α 3 protein abundance ( P = 0.046). Exercise transiently depressed maximal Na + -K + -ATPase activity ( P = 0.004), but Na + -K + -ATPase content was unaltered throughout recovery. Exercise immediately increased RNAP II mRNA by 2.6-fold ( P = 0.011) but had no effect on eIF-4E and 4E-BP1 mRNA. Thus a single bout of prolonged submaximal exercise induced isoform-specific Na + -K + -ATPase responses, increasing α 1 , α 3 , and β 2 mRNA but only α 3 protein expression. Exercise also increased mRNA expression of RNAP II, a gene initiating transcription, but not of eIF-4E and 4E-BP1, key genes initiating protein translation.
Publisher: Informa UK Limited
Date: 23-06-2014
DOI: 10.3109/10715762.2014.927579
Abstract: Influenza A virus infects resident alveolar macrophages in the respiratory tract resulting in Toll like receptor 7 (TLR7) activation that triggers an inflammatory response to resolve the infection. Macrophages are also major sources of reactive oxygen species (ROS) via the NOX2-containing NADPH oxidase. Although ROS are crucial for pathogen clearance, in response to influenza A virus, ROS are touted as being culprit mediators of the lung tissue injury. The aim of the present study was to determine whether influenza A virus infection and TLR7 activation of macrophages, results in alterations in their ROS production. Here we demonstrate using immunofluorescence that influenza A virus (Hong Kong X-31 strain H3N2) internalizes in RAW264.7 cells and mouse alveolar macrophages within 1 h, resulting in a significant enhancement in the stimulated NOX2 oxidase-dependent oxidative burst, although virus had no effect on basal ROS. The specific TLR7 agonist imiquimod (10 μg/ml) elevated basal superoxide production and, in a similar fashion to influenza A virus, enhanced NOX2 oxidase-dependent oxidative burst. By contrast, the TLR3 agonist, poly I:C (1-100 μg/ml) failed to influence the oxidative burst to NOX2 oxidase. A peptide corresponding to the region 337-348 on p47phox conjugated to a HIV-tat, designed to inhibit the phosphorylation of Ser346 on p47phox suppressed the influenza A virus- and imiquimod-induced enhancement in the oxidative burst. In conclusion, this study demonstrates for the first time that influenza A virus and TLR7 activation enhance the NOX2 oxidase-dependent oxidative burst in macrophages, which might underpin the acute lung injury to influenza A virus infection.
Publisher: Mary Ann Liebert Inc
Date: 08-2012
DOI: 10.1089/HUM.2011.210
Publisher: Wiley
Date: 30-12-2013
DOI: 10.1096/FJ.13-245894
Abstract: In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF-β proteins of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor-derived factors induces cachexia, we used recombinant serotype 6 adeno-associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ~10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibited weight loss in a dose-dependent manner, to a maximum of -12.4% (-4.2±1.1 g). These reductions in body mass in rAAV6:activin-injected mice correlated inversely with elevated serum activin A levels (7- to 24-fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy-related ubiquitin ligases, decreased Akt/mTOR-mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia.
Publisher: Wiley
Date: 12-07-2010
DOI: 10.1096/FJ.10-159608
Abstract: Sarcopenia is the progressive loss of skeletal muscle mass and function with advancing age, leading to reduced mobility and quality of life. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the decline in mass and function of muscles of aged mice and that apoptosis would be reduced. Eighteen-month-old C57BL/6 mice were treated for 14 wk with a once-weekly injection of saline (control, n=9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg n=12). PF-354 prevented the age-related reduction in body mass and increased soleus, gastrocnemius, and quadriceps muscle mass (P<0.05). PF-354 increased fiber cross-sectional area by 12% and enhanced maximum in situ force of tibialis anterior (TA) muscles by 35% (P<0.05). PF-354 increased the proportion of type IIa fibers by 114% (P<0.01) and enhanced activity of oxidative enzymes (SDH) by 39% (P<0.01). PF-354 reduced markers of apoptosis in TA muscle cross-sections by 56% (P<0.03) and reduced caspase3 mRNA by 65% (P<0.04). Antibody-directed myostatin inhibition attenuated the decline in mass and function of muscles of aging mice, in part, by reducing apoptosis. These observations identify novel roles for myostatin in regulation of muscle mass and highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia.
Publisher: Oxford University Press (OUP)
Date: 31-07-2014
DOI: 10.1093/HMG/DDU388
Publisher: Public Library of Science (PLoS)
Date: 08-04-2013
Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 05-2010
Publisher: Wiley
Date: 08-2022
DOI: 10.1113/JP283017
Abstract: We investigated whether digoxin lowered muscle Na + ,K + ‐ATPase (NKA), impaired muscle performance and exacerbated exercise K + disturbances. Ten healthy adults ingested digoxin (0.25 mg DIG) or placebo (CON) for 14 days and performed quadriceps strength and fatiguability, finger flexion (FF, 105% peak‐workrate , 3 × 1 min, fourth bout to fatigue) and leg cycling (LC, 10 min at 33% and 67% , 90% to fatigue) trials using a double‐blind, crossover, randomised, counter‐balanced design. Arterial (a) and antecubital venous (v) blood was s led (FF, LC) and muscle biopsied (LC, rest, 67% , fatigue, 3 h after exercise). In DIG, in resting muscle, [ 3 H]‐ouabain binding site content (OB‐F ab ) was unchanged however, bound‐digoxin removal with Digibind revealed total ouabain binding (OB+F ab ) increased (8.2%, P = 0.047), indicating 7.6% NKA–digoxin occupancy. Quadriceps muscle strength declined in DIG (−4.3%, P = 0.010) but fatiguability was unchanged. During LC, in DIG (main effects), time to fatigue and [K + ] a were unchanged, whilst [K + ] v was lower ( P = 0.042) and [K + ] a‐v greater ( P = 0.004) than in CON with exercise (main effects), muscle OB‐F ab was increased at 67% (per wet‐weight, P = 0.005 per protein P = 0.001) and at fatigue (per protein, P = 0.003), whilst [K + ] a , [K + ] v and [K + ] a‐v were each increased at fatigue ( P = 0.001). During FF, in DIG (main effects), time to fatigue, [K + ] a , [K + ] v and [K + ] a‐v were unchanged with exercise (main effects), plasma [K + ] a , [K + ] v , [K + ] a‐v and muscle K + efflux were all increased at fatigue ( P = 0.001). Thus, muscle strength declined, but functional muscle NKA content was preserved during DIG, despite elevated plasma digoxin and muscle NKA–digoxin occupancy, with K + disturbances and fatiguability unchanged. image The Na + ,K + ‐ATPase (NKA) is vital in regulating skeletal muscle extracellular potassium concentration ([K + ]), excitability and plasma [K + ] and thereby also in modulating fatigue during intense contractions. NKA is inhibited by digoxin, which in cardiac patients lowers muscle functional NKA content ([ 3 H]‐ouabain binding) and exacerbates K + disturbances during exercise. In healthy adults, we found that digoxin at clinical levels surprisingly did not reduce functional muscle NKA content, whilst digoxin removal by Digibind antibody revealed an ∼8% increased muscle total NKA content. Accordingly, digoxin did not exacerbate arterial plasma [K + ] disturbances or worsen fatigue during intense exercise, although quadriceps muscle strength was reduced. Thus, digoxin treatment in healthy participants elevated serum digoxin, but muscle functional NKA content was preserved, whilst K + disturbances and fatigue with intense exercise were unchanged. This resilience to digoxin NKA inhibition is consistent with the importance of NKA in preserving K + regulation and muscle function.
Publisher: American Physiological Society
Date: 09-2011
DOI: 10.1152/AJPREGU.00121.2011
Abstract: Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for % of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12 LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg −1 ·wk −1 , LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8–10% ( P 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment ( P 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection ( P 0.05) but was not improved with PF-354 treatment ( P 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively ( P 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice ( P 0.05) but was not different in PF-354-treated tumor-bearing mice ( P 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
DOI: 10.1161/STROKEAHA.117.019136
Abstract: Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. We tested the efficacy of acute (1.5 hours) or delayed (1–3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7–14 weeks) and aged mice (20–22 months) of both sexes, as well as adult marmosets of either sex. We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.CLNU.2013.06.013
Abstract: The non-essential amino acid, glycine, is often considered biologically neutral, but some studies indicate that it could be an effective anti-inflammatory agent. Since inflammation is central to the development of cancer cachexia, glycine supplementation represents a simple, safe and promising treatment. We tested the hypothesis that glycine supplementation reduces skeletal muscle inflammation and preserves muscle mass in tumor-bearing mice. To induce cachexia, CD2F1 mice received a subcutaneous injection of PBS (control, n = 12) or C26 tumor cells (n = 32) in accordance with the protocols developed by Murphy et al. [Murphy KT, Chee A, Trieu J, Naim T, Lynch GS. Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Models Mech 2012 (4):533-545.]. Subcutaneous injections of glycine (n = 16) or PBS (n = 16) were administered daily for 21 days and at the conclusion of treatment, selected muscles, tumor and adipose tissue were collected and prepared for Real-Time RT-PCR or western blot analysis. Glycine attenuated the loss of fat and muscle mass, blunted increases in markers of inflammation (F4/80, P = 0.01 & IL-6 mRNA, P = 0.01) and atrophic signaling (MuRF, P = 0.047 atrogin-1, P = 0.04 LC3B, P = 0.06 and BNIP3, P = 0.10) and tended to attenuate the loss of body mass (P = 0.07), muscle function (P = 0.06), and oxidative stress (GSSG/GSH, P = 0.06 and DHE, P = 0.07) seen in tumor-bearing mice. Preliminary studies that compared the effect of glycine administration with isonitrogenous doses of alanine or citrulline showed that the observed protective effect was specific to glycine. Glycine protects skeletal muscle from cancer-induced wasting and loss of function, reduces the oxidative and inflammatory burden, and reduces the expression of genes associated with muscle protein breakdown in cancer cachexia. Importantly, these effects were glycine specific.
Publisher: Wiley
Date: 26-08-2021
DOI: 10.1002/RCO2.50
Abstract: Cachexia is a debilitating complication of cancer characterized by progressive wasting and weakness of skeletal muscles that reduces quality of life and can compromise survival. Many anticancer treatments, such as chemotherapy, also cause muscle wasting, which impairs the response to treatment. Given that many cancer patients present with cachexia at the initiation of treatment, we investigated whether cachectic mice were susceptible to chemotherapy‐induced muscle wasting and to investigate contributing mechanisms, including the dysregulation of microRNAs (miRs). Cachectic colon‐26 (C‐26) tumour‐bearing mice were given 5‐fluourouracil (5‐FU) chemotherapy or vehicle treatment and analysed for muscle mass, fibre size and composition, and miR expression. Mechanisms were validated in vitro using C2C12 cell culture and miR mimics and inhibitors and were confirmed in vivo by injecting muscles of 5‐FU‐treated cachectic mice with recombinant adeno‐associated viral (rAAV) vectors encoding a miR sponge. In cachectic tumour‐bearing mice, 5‐FU chemotherapy exacerbated the loss of skeletal muscle mass compared with vehicle treatment (by −12% to −20%, P 0.05). miR expression profiling, quantitative real‐time PCR, and in vitro analyses revealed contributing mechanisms including miR‐351‐3p‐dependent ERK2 inhibition. Intramuscular injection of rAAV vectors encoding a sponge to reduce miR‐351‐3p expression in 5‐FU‐treated cachectic mice enhanced ERK phosphorylation (+18%, P 0.05) and increased muscle fibre size (+15%, P 0.01). Hsa‐miR‐125a‐3p shares similar predicted gene targets as mmu‐miR‐351‐3p, and its inhibition in human muscle cells in vitro prevented 5‐FU‐induced atrophy ( P 0.001) and increased ERK phosphorylation ( P 0.001). The findings implicate miR‐351‐3p‐mediated ERK2 inhibition as a contributing mechanism in chemotherapy‐induced muscle wasting in mice with cancer cachexia and that its inhibition is a promising adjunct therapy for preserving muscles during cancer treatment.
Publisher: MDPI AG
Date: 18-01-2022
Abstract: Cancer cachexia is the progressive muscle wasting and weakness experienced by many cancer patients. It can compromise the response to gold standard cancer therapies, impair functional capacity and reduce overall quality of life. Cancer cachexia accounts for nearly one-third of all cancer-related deaths and has no effective treatment. The pathogenesis of cancer cachexia and its progression is multifactorial and includes increased oxidative stress derived from both the tumor and the host immune response. Antioxidants have therapeutic potential to attenuate cancer-related muscle loss, with polyphenols, a group of plant-derived antioxidants, being the most widely investigated. This review describes the potential of these plant-derived antioxidants for treating cancer cachexia.
Publisher: SAGE Publications
Date: 10-02-2010
Abstract: Cerebral infarct volume is typically smaller in premenopausal females than in age-matched males after ischemic stroke, but the underlying mechanisms are poorly understood. In this study we provide evidence in mice that this gender difference only occurs when the ischemic brain is reperfused. The limited tissue salvage achieved by reperfusion in male mice is associated with increased expression of proinflammatory proteins, including cyclooxygenase-2 (Cox-2), Nox2, and vascular cell adhesion molecule-1 (VCAM-1), and infiltration of Nox2-containing T lymphocytes into the infarcted brain, whereas such changes are minimal in female mice after ischemia–reperfusion (I-R). Infarct volume after I-R was no greater at 72 h than at 24 h in either gender. Infarct development was Nox2 dependent in male but not in female mice, and Nox2 within the infarct was predominantly localized in T lymphocytes. Stroke resulted in an ∼15-fold increase in Nox2-dependent superoxide production by circulating, but not spleen-derived, T lymphocytes in male mice, and this was ∼sevenfold greater than in female mice. These circulating immune cells may thus represent a major and previously unrecognized source of superoxide in the acutely ischemic and reperfused brain of males (and potentially in postmenopausal females). Our findings provide novel insights into mechanisms that could be therapeutically targeted in acute ischemic stroke patients who receive thrombolysis therapy to induce cerebral reperfusion.
Publisher: American Physiological Society
Date: 07-2007
DOI: 10.1152/JAPPLPHYSIOL.00236.2006
Abstract: The Na + -K + -ATPase enzyme is vital in skeletal muscle function. We investigated the effects of acute high-intensity interval exercise, before and following high-intensity training (HIT), on muscle Na + -K + -ATPase maximal activity, content, and isoform mRNA expression and protein abundance. Twelve endurance-trained athletes were tested at baseline, pretrain, and after 3 wk of HIT (posttrain), which comprised seven sessions of 8 × 5-min interval cycling at 80% peak power output. Vastus lateralis muscle was biopsied at rest (baseline) and both at rest and immediately postexercise during the first (pretrain) and seventh (posttrain) training sessions. Muscle was analyzed for Na + -K + -ATPase maximal activity (3- O-MFPase), content ([ 3 H]ouabain binding), isoform mRNA expression (RT-PCR), and protein abundance (Western blotting). All baseline-to-pretrain measures were stable. Pretrain, acute exercise decreased 3- O-MFPase activity [12.7% (SD 5.1), P 0.05], increased α 1 , α 2 , and α 3 mRNA expression (1.4-, 2.8-, and 3.4-fold, respectively, P 0.05) with unchanged β-isoform mRNA or protein abundance of any isoform. In resting muscle, HIT increased ( P 0.05) 3- O-MFPase activity by 5.5% (SD 2.9), and α 3 and β 3 mRNA expression by 3.0- and 0.5-fold, respectively, with unchanged Na + -K + -ATPase content or isoform protein abundance. Posttrain, the acute exercise induced decline in 3- O-MFPase activity and increase in α 1 and α 3 mRNA each persisted ( P 0.05) the postexercise 3- O-MFPase activity was also higher after HIT ( P 0.05). Thus HIT augmented Na + -K + -ATPase maximal activity despite unchanged total content and isoform protein abundance. Elevated Na + -K + -ATPase activity postexercise may contribute to reduced fatigue after training. The Na + -K + -ATPase mRNA response to interval exercise of increased α- but not β-mRNA was largely preserved posttrain, suggesting a functional role of α mRNA upregulation.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.CELL.2015.08.031
Abstract: The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
Publisher: The Company of Biologists
Date: 2012
DOI: 10.1242/DMM.008839
Abstract: Cancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for & % of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18-20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (-27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (-10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia.
Publisher: Wiley
Date: 04-2004
Publisher: Public Library of Science (PLoS)
Date: 03-02-2011
Publisher: American Physiological Society
Date: 06-2008
DOI: 10.1152/AJPHEART.00985.2007
Abstract: We determined the cardiovascular effects of chronic β 2 -adrenoceptor (β 2 -AR) stimulation in vivo and examined the mechanism for the previously observed prolonged diastolic relaxation. Rats (3 mo old n = 6), instrumented with implantable radiotelemeters, received the selective β 2 -AR agonist formoterol (25 μg·kg −1 ·day −1 ip) for 4 wk, with selected cardiovascular parameters measured daily throughout this period, and for a further 7 days after cessation of treatment. Chronic β 2 -AR stimulation was associated with an increase in heart rate (HR) of 17% ( days 1– 14) and 5% ( days 15–28) a 11% ( days 1– 14) and 6% ( days 15– 28) decrease in mean arterial blood pressure and a 24% ( days 1– 14) increase in the rate of cardiac relaxation (−dP/d t) compared with initial values ( P 0.05). Cessation of β 2 -AR stimulation resulted in an 8% decrease in HR and a 7% decrease in −dP/d t, compared with initial values ( P 0.05). The prolonged cardiac relaxation with chronic β 2 -AR stimulation was associated with a 30% decrease in the maximal rate ( V max ) of sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) activity, likely attributed to a 50% decrease in SERCA2a protein ( P 0.05). glycogen synthase kinase-3β (GSK-3β) has been implicated as a negative regulator of SERCA2 gene transcription, and we observed a ∼60% decrease ( P 0.05) in phosphorylated GSK-3β protein after chronic β 2 -AR stimulation. Finally, we found a 40% decrease ( P 0.05) in the mRNA expression of the novel A kinase anchoring protein AKAP18, also implicated in β 2 -AR-mediated cardiac relaxation. These findings highlight some detrimental cardiovascular effects of chronic β 2 -AR agonist administration and identify concerns for their current and future use for treating asthma or for conditions where muscle wasting and weakness are indicated.
Publisher: Wiley
Date: 30-11-2010
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.AJPATH.2016.08.008
Abstract: Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established. Later stage treatment of mdx or dko mice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15-treated dko mice but unchanged in TA muscles of treated mdx mice and diaphragm of treated mdx and dko mice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dko mice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
DOI: 10.1158/0008-5472.CAN-18-1207
Abstract: These findings demonstrate that MasR activation has multiple benefits of being orexigenic, anticachectic, and antitumorigenic, revealing it as a potential adjunct therapy for cancer. See related commentary by Rupert et al., p. 699
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-07-2016
DOI: 10.1126/SCITRANSLMED.AAC4976
Abstract: Muscle-directed Smad7 gene delivery prevents the loss of skeletal muscle mass and strength in mouse models of cachexia, an important contributor to poor prognosis in patients with advanced cancer.
Publisher: Wiley
Date: 29-10-2012
Abstract: In the present study, we tested whether polycystic kidney disease (PKD) is associated with renal tissue hypoxia and oxidative stress, which, in turn, contribute to the progression of cystic disease and hypertension. Lewis polycystic kidney (LPK) rats and Lewis control (Lewis) rats were treated with tempol (1 mmol/L in drinking water) from 3 to 13 weeks of age or remained untreated. The LPK rats developed polyuria, uraemia and proteinuria. At 13 weeks of age, LPK rats had greater mean arterial pressure (1.5-fold), kidney weight (sixfold) and plasma creatinine (3.5-fold) than Lewis rats. Kidneys from LPK rats were cystic and fibrotic. Renal hypoxia was evidenced by staining for pimonidazole adducts and hypoxia-inducible factor (HIF)-1α in cells lining renal cysts and upregulation of HIF-1α and its downstream targets vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1) and heme oxygenase 1 (HO-1). However, total HO activity did not differ greatly between kidney tissue from LPK compared with Lewis rats. Renal oxidative and/or nitrosative stress was evidenced by ninefold greater immunofluorescence for 3-nitrotyrosine in kidney tissue from LPK compared with Lewis rats and a > 10-fold upregulation of mRNA for p47phox and gp91phox. Total renal superoxide dismutase (SOD) activity was sevenfold less and expression of SOD1 mRNA was 70% less in kidney tissue from LPK compared with Lewis rats. In LPK rats, tempol treatment reduced immunofluorescence for 3-nitrotyrosine and HIF1A mRNA while upregulating VEGF and p47phox mRNA expression, but otherwise had little impact on disease progression, renal tissue hypoxia or hypertension. Our findings do not support the hypothesis that oxidative stress drives hypoxia and disease progression in PKD.
Publisher: Wiley
Date: 18-11-2008
DOI: 10.1113/EXPPHYSIOL.2008.042796
Abstract: Exercise increases Na(+)-K(+) pump isoform gene expression and elevates muscle reactive oxygen species (ROS). We investigated whether enhanced ROS scavenging induced with the antioxidant N-acetylcysteine (NAC) blunted the increase in Na(+)-K(+) pump mRNA during repeated contractions in human and rat muscle. In experiment 1, well-trained subjects received saline or NAC intravenously prior to and during 45 min cycling. Vastus lateralis muscle biopsies were taken pre-infusion and following exercise. In experiment 2, isolated rat extensor digitorum longus muscles were pre-incubated without or with 10 mm NAC and then rested or stimulated electrically at 60 Hz for 90 s. After 3 h recovery, muscles were frozen. In both experiments, the muscles were analysed for Na(+)-K(+) pump alpha(1), alpha(2), alpha(3), beta(1), beta(2) and beta(3) mRNA. In experiment 1, exercise increased alpha(2) mRNA by 1.0-fold (P = 0.03), but alpha(2) mRNA was reduced by 0.40-fold with NAC (P = 0.03). Exercise increased alpha(3), beta(1) and beta(2) mRNA by 2.0- to 3.4-fold (P 0.32). Neither exercise nor NAC altered alpha(1) or beta(3) mRNA (P > 0.31). In experiment 2, electrical stimulation increased alpha(1), alpha(2) and alpha(3) mRNA by 2.3- to 17.4-fold (P 0.07). Electrical stimulation almost completely reduced beta(1) mRNA but only in the presence of NAC (P 0.09). In conclusion, NAC attenuated the increase in Na(+)-K(+) pump alpha(2) mRNA with exercise in human muscle and all alpha isoforms with electrical stimulation in rat muscle. This indicates a regulatory role for ROS in Na(+)-K(+) pump alpha isoform mRNA in mammalian muscle during repeated contractions.
Publisher: Wiley
Date: 22-09-2006
Publisher: American Physiological Society
Date: 06-2021
DOI: 10.1152/AJPCELL.00513.2020
Abstract: The dystrophin-glycoprotein complex (DGC) is a multiprotein structure required to maintain muscle fiber membrane integrity, transmit force by linking the actin cytoskeleton with the extracellular matrix, and maintain muscle homeostasis. Membrane localization of dystrophin is perturbed in muscles wasting as a consequence of cancer cachexia, tenotomy, and advanced aging, which are all associated with low level, chronic inflammation. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan. To test the contribution of amino acid phosphorylation to muscle fiber size changes, dystrophin constructs with phospho-null and phosphomimetic mutations were transfected into C2C12 muscle cells or AAV-293 cells in the presence or absence of kinase inhibitors/activators to assess effects on myotube diameter and protein function. Overexpression of a dystrophin construct with a phospho-null mutation at S3059 in vitro reduced myotube size in healthy C2C12 cells. Conversely overexpression of a phosphomimetic mutation at S3059 attenuated inflammation-induced myotube atrophy. Increased ERK activation by addition of phorbol myristate acetate (PMA) also reduced inflammation-associated myotube atrophy and increased the interaction between dystrophin and β-dystroglycan. These findings demonstrate a link between increased ERK activation, dystrophin S3059 phosphorylation, stabilization of the DGC, and the regulation of muscle fiber size. Interventions that increase dystrophin S3059 phosphorylation to promote stronger binding of dystrophin to β-dystroglycan may have therapeutic potential for attenuation of inflammation-associated muscle wasting.
Publisher: American Physiological Society
Date: 04-2011
DOI: 10.1152/JAPPLPHYSIOL.01183.2010
Abstract: Counteracting the atrophy of skeletal muscle associated with disuse has significant implications for minimizing the wasting and weakness in plaster casting, joint immobilization, and other forms of limb unloading, with relevance to orthopedics, sports medicine, and plastic and reconstructive surgery. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the loss of muscle mass and functional capacity in mice during 14 or 21 days of unilateral hindlimb casting. Twelve-week-old C57BL/10 mice were subjected to unilateral hindlimb plaster casting or served as controls. Mice received subcutaneous injections of saline or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg n = 6–9) on days 0 and 7 and were tested for muscle function on day 14, or were treated on days 0, 7, and 14 and tested for muscle function on day 21. Hindlimb casting reduced muscle mass, fiber size, and function of isolated soleus and extensor digitorum longus (EDL) muscles ( P 0.05). PF-354 attenuated the loss of muscle mass, fiber size, and function with greater effects after 14 days than after 21 days of casting, when wasting and weakness had plateaued ( P 0.05). Antibody-directed myostatin inhibition therefore attenuated the atrophy and loss of functional capacity in muscles from mice subjected to unilateral hindlimb casting with reductions in muscle size and strength being most apparent during the first 14 days of disuse. These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for disuse atrophy especially within the first 2 wk of disuse.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41371-022-00723-8
Abstract: Blood pressure(BP) management interventions have been shown to be more effective when accompanied by appropriate patient education. As high BP remains poorly controlled, there may be gaps in patient knowledge and education. Therefore, this study aimed to identify specific content and delivery preferences for information to support BP management among Australian adults from the general public. Given that BP management is predominantly undertaken by general practitioners(GPs), information preferences to support BP management were also ascertained from a small s le of Australian GPs. An online survey of adults was conducted to identify areas of concern for BP management to inform content preferences and preferred format for information delivery. A separate online survey was also delivered to GPs to determine preferred information sources to support BP management. Participants were recruited via social media. General public participants ( n = 465) were mostly female (68%), years (57%) and 49% were taking BP-lowering medications. The management of BP without medications, and role of lifestyle in BP management were of concern among 30% and 26% of adults respectively. Most adults (73%) preferred to access BP management information from their GP. 57% of GPs (total n = 23) preferred information for supporting BP management to be delivered via one-page summaries. This study identified that Australian adults would prefer more information about the management of BP without medications and via lifestyle delivered by their GP. This could be achieved by providing GPs with one-page summaries on relevant topics to support patient education and ultimately improve BP management.
Publisher: Public Library of Science (PLoS)
Date: 29-10-2012
Publisher: American Physiological Society
Date: 15-05-2013
DOI: 10.1152/AJPREGU.00057.2013
Abstract: Loss of skeletal muscle mass and function (cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20–29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls ( P 0.03). MoCR mice exhibited impaired rotarod performance and grip strength ( P 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity ( P 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue ( P 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases.
Publisher: Elsevier BV
Date: 2011
Publisher: Wiley
Date: 16-03-2013
DOI: 10.1002/IJC.28128
Abstract: Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers. Cachexia reduces mobility and quality of life and accounts for 20-30% of all cancer-related deaths. Activation of the renin-angiotensin system causes skeletal muscle wasting and weakness. We tested the hypothesis that treatment with the angiotensin converting enzyme (ACE) inhibitor, perindopril, would enhance whole body and skeletal muscle function in cachectic mice bearing Colon-26 (C-26) tumors. CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C-26 tumor cells inducing either a mild or severe cachexia. The following day, one cohort of C-26 mice began receiving perindopril in their drinking water (4 mg kg(-1) day(-1) ) for 21 days. In mild and severe cachexia, perindopril increased measures of whole body function (grip strength and rotarod) and reduced fatigue in isolated contracting diaphragm muscle strips (p < 0.05). In severely cachectic mice, perindopril reduced tumor growth, improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ (p < 0.05), which was associated with increased oxidative enzyme capacity (succinate deyhydrogenase, p < 0.05). Perindopril attenuated the increase in MuRF-1 and IL-6 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased. These findings support the therapeutic potential of ACE inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials. Since ACE inhibition alone did not enhance body or muscle mass, co-treatment with an anabolic agent may be required to address these aspects of cancer cachexia.
Publisher: Informa Healthcare
Date: 10-01-2012
DOI: 10.1517/14728214.2012.652946
Abstract: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and weakness. It affects most patients with advanced cancers, reduces quality of life and accounts for more than 20% of all cancer-related deaths. A number of promising therapies for cancer cachexia are in development, including appetite stimulants, anti-inflammatory drugs and those targeting catabolism. However, the multifactorial pathogenesis indicates strongly that the most effective treatments will come from drug combination approaches. Drug treatments should ideally be combined with exercise training to maximize efficacy and ultimately reduce mortality and enhance the quality of life of patients with cancer cachexia.
Publisher: Wiley
Date: 29-09-2011
DOI: 10.1111/J.1748-1716.2011.02344.X
Abstract: Production of reactive oxygen species (ROS) in skeletal muscle is markedly increased during exercise and may be essential for exercise adaptation. We, therefore, investigated the effects of infusion with the antioxidant N-acetylcysteine (NAC) on exercise-induced activation of signalling pathways and genes involved in exercise adaptation in human skeletal muscle. Subjects completed two exercise tests, 7 days apart, with saline (control, CON) or NAC infusion before and during exercise. Exercise tests comprised of cycling at 71% VO(2peak) for 45 min, and then 92% VO(2peak) to fatigue, with vastus lateralis biopsies at pre-infusion, after 45-min cycling and at fatigue. Analysis was conducted on the mitogen-activated protein kinase signalling pathways, demonstrating that NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK. Nuclear factor-κB p65 phosphorylation was unaffected by exercise however, it was reduced in NAC at fatigue by 14% (P < 0.05) compared with pre-infusion. Analysis of exercise and/or ROS-sensitive genes demonstrated that exercise-induced mRNA expression is ROS dependent of MnSOD, but not PGC-1α, interleukin-6, monocyte chemotactic protein-1, or heat-shock protein 70. These results suggest that inhibition of ROS attenuates some skeletal muscle cell signalling pathways and gene expression involved in adaptations to exercise.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPREGU.00007.2012
Abstract: The role of the renin-angiotensin system (RAS) in vasoregulation is well established, but a localized RAS exists in multiple tissues and exerts erse functions including autonomic control and thermogenesis. The role of the RAS in the maintenance and function of skeletal muscle is not well understood, especially the role of angiotensin peptides, which appear to contribute to muscle atrophy. We tested the hypothesis that mice lacking the angiotensin type 1A receptor (AT 1A −/− ) would exhibit enhanced whole body and skeletal muscle function and improved regeneration after severe injury. Despite 18- to 20-wk-old AT 1A −/− mice exhibiting reduced muscle mass compared with controls ( P 0.05), the tibialis anterior (TA) muscles produced a 25% higher maximum specific (normalized) force ( P 0.05). Average fiber cross-sectional area (CSA) and fiber oxidative capacity was not different between groups, but TA muscles from AT 1A −/− mice had a reduced number of muscle fibers as well as a higher proportion of type IIx/b fibers and a lower proportion of type IIa fibers ( P 0.05). Measures of whole body function (grip strength, rotarod performance, locomotor activity) were all improved in AT 1A −/− mice ( P 0.05). Surprisingly, the recovery of muscle mass and fiber CSA following myotoxic injury was impaired in AT 1A −/− mice, in part by impaired myoblast fusion, prolonged collagen infiltration and inflammation, and delayed expression of myogenic regulatory factors. The findings support the therapeutic potential of RAS inhibition for enhancing whole body and skeletal muscle function, but they also reveal the importance of RAS signaling in the maintenance of muscle mass and for normal fiber repair after injury.
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/S41467-017-00057-X
Abstract: The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.
Location: Australia
No related grants have been discovered for Kate Murphy.