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 macronutrient-derivative 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.
Some studies report greater muscle hypertrophy during resistance exercise (RE) training from supplement timing (i.e., the strategic consumption of protein and carbohydrate before and/or after each ...workout). However, no studies have examined whether this strategy provides greater muscle hypertrophy or strength development compared with supplementation at other times during the day. The purpose of this study was to examine the effects of supplement timing compared with supplementation in the hours not close to the workout on muscle-fiber hypertrophy, strength, and body composition during a 10-wk RE program.
In a single-blind, randomized protocol, resistance-trained males were matched for strength and placed into one of two groups; the PRE-POST group consumed a supplement (1 g x kg(-1) body weight) containing protein/creatine/glucose immediately before and after RE. The MOR-EVE group consumed the same dose of the same supplement in the morning and late evening. All assessments were completed the week before and after 10 wk of structured, supervised RE training. Assessments included strength (1RM, three exercises), body composition (DEXA), and vastus lateralis muscle biopsies for determination of muscle fiber type (I, IIa, IIx), cross-sectional area (CSA), contractile protein, creatine (Cr), and glycogen content.
PRE-POST demonstrated a greater (P < 0.05) increase in lean body mass and 1RM strength in two of three assessments. The changes in body composition were supported by a greater (P < 0.05) increase in CSA of the type II fibers and contractile protein content. PRE-POST supplementation also resulted in higher muscle Cr and glycogen values after the training program (P < 0.05).
Supplement timing represents a simple but effective strategy that enhances the adaptations desired from RE-training.
Director's report Hayes, Alan
Family Matters,
01/2013
92
Journal Article
Recenzirano
Odprti dostop
Over the life course, Australian families undergo many transitions and are influenced by many social and economic factors.
The variety of influences on the wellbeing of Australian families is ...reflected in the breadth of the Institute's evolving program. The Institute provides a valuable service by delivering sound, objective evidence for policy-makers, researchers, community practitioners and the Australian community., Over the life course, Australian families undergo many transitions and are influenced by many social and economic factors. The variety of influences on the wellbeing of Australian families is reflected in the breadth of the Institute's evolving program. The Institute provides a valuable service by delivering sound, objective evidence for policy-makers, researchers, community practitioners and the Australian community.
The bone-derived protein osteocalcin (OC), in its undercarboxylated (ucOC) form, has a beneficial effect on energy metabolism and may be a future therapeutic target for metabolic diseases. Increasing ...evidence suggests a link between ucOC and cardiovascular disease (CVD) development; however, the exact relationship is conflicting and unclear.
The aim of this review was to summarise the current research examining the interaction between OC and vascular dysfunction, the initiating stage in the development of atherosclerosis and CVD.
In humans, the association between OC and vascular function is inconsistent. Several studies report that total OC (tOC) is associated with adverse function or beneficial function, whereas others report that tOC and ucOC has no effect on vascular function. The conflicting data are likely due to several methodological inconsistencies, in particular the lack of studies reporting circulating ucOC levels. In animal models, the direct administration of ucOC to isolated blood vessels ex vivo produced minimal changes in endothelial function, but importantly, no adverse responses. Finally, in human endothelial and vascular smooth muscle cells, ucOC treatment did not influence classical markers of cellular function, including endothelin-1, vascular adhesion molecule-1 and monocyte chemoattractant protein-1 after exposure to high glucose and inflammatory conditions. The lack of adverse effects in ex vivo and in vitro studies suggests that ucOC may be targeted as a future therapeutic for metabolic diseases, without the risk of detrimental effects in the vasculature. However, further studies are needed to confirm these findings and to investigate whether there is a direct beneficial influence of ucOC.
•ucOC is implicated in the regulation of glucose homeostasis; but its role in the vasculature has been minimally reported.•Studies which examine the association between ucOC and vascular function in humans often report inconsistent outcomes.•In addition, ex vivo and in vitro studies have reported that ucOC likely does not directly regulate endothelial function.•ucOC may be targeted as a therapeutic treatment for metabolic diseases without a risk of adverse effects in the vasculature.
There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. Osteocalcin, an osteoblast derived protein, exists in two forms, carboxylated ...and undercarboxylated osteocalcin. Undercarboxylated osteocalcin has been linked to the regulation of metabolic functions, including glucose and lipid metabolism. Features of atherosclerosis have been associated with circulating osteocalcin; however, this association is often conflicting and unclear. Therefore, the aim of this review is to examine the evidence for a role of osteocalcin in atherosclerosis development and progression, and in particular endothelial dysfunction and vascular calcification. The current literature suggests that undercarboxylated osteocalcin stimulates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to upregulate nitric oxide and nuclear factor kappa β (NF-кβ) in vascular cells, possibly protecting endothelial function and preventing atherogenesis. However, this effect may be mediated by metabolic factors, such as improvements in insulin signaling, rather than through a direct effect on the vasculature. Total osteocalcin is frequently associated with vascular calcification, an association that may occur as a result of vascular cells eliciting an osteogenic phenotype. Whether osteocalcin acts as a mediator or a marker of vascular calcification is currently unclear. As such, further studies that examine each form of osteocalcin are required to elucidate if it is a mediator of atherogenesis, and whether it functions independently of metabolic factors.
The Toronto School of Theology (TST), which is the name used for both a consortium of seven colleges founded in 1969 and a not-for-profit corporation established a year later, designed a governance ...for itself in 1970 that promoted the co-operation of the member institutions while safeguarding their autonomy. The TST’s bylaw—which entrenched conflicts of interest, confused corporation with consortium, loaded councils with both governance and administrative functions, assigned similar functions to different groups, and obscured lines of accountability—helped preserve the member colleges from unwelcome changes. Subsequently, however, two significant moments brought modifications to TST’s governance that may have been unavoidable but that subverted the consortium’s original controlling vision. These moments were TST’s first Memorandum of Agreement with the University of Toronto in 1979 and the university’s imposition of its new quality assurance regime in 2011. TST is now frequently caught between two masters: the member colleges that own it and the university that treats it, in many respects, as one of its academic units.
Macrophages are key regulators of developmental processes, including those involved in mammary gland development. We have previously demonstrated that the atypical chemokine receptor ACKR2 ...contributes to the control of ductal epithelial branching in the developing mammary gland by regulating macrophage dynamics. ACKR2 is a chemokine-scavenging receptor that mediates its effects through collaboration with inflammatory chemokine receptors (iCCRs). Here, we reveal reciprocal regulation of branching morphogenesis in the mammary gland, whereby stromal ACKR2 modulates levels of the shared ligand CCL7 to control the movement of a key population of CCR1-expressing macrophages to the ductal epithelium. In addition, oestrogen, which is essential for ductal elongation during puberty, upregulates CCR1 expression on macrophages. The age at which girls develop breasts is decreasing, which raises the risk of diseases including breast cancer. This study presents a previously unknown mechanism controlling the rate of mammary gland development during puberty and highlights potential therapeutic targets.
Polyamines have been shown to be absolutely required for protein synthesis and cell growth. The serine/threonine kinase, the mechanistic target of rapamycin complex 1 (mTORC1), also plays a ...fundamental role in the regulation of protein turnover and cell size, including in skeletal muscle, where mTORC1 is sufficient to increase protein synthesis and muscle fiber size, and is necessary for mechanical overload-induced muscle hypertrophy. Recent evidence suggests that mTORC1 may regulate the polyamine metabolic pathway; however, there is currently no evidence in skeletal muscle. This study examined changes in polyamine pathway proteins during muscle hypertrophy induced by mechanical overload (7 d), with and without the mTORC1 inhibitor, rapamycin, and during muscle atrophy induced by food deprivation (48 h) and denervation (7 d) in mice. Mechanical overload induced an increase in mTORC1 signalling, protein synthesis and muscle mass, and these were associated with rapamycin-sensitive increases in adenosylmethione decarboxylase 1 (Amd1), spermidine synthase (SpdSyn) and c-Myc. Food deprivation decreased mTORC1 signalling, protein synthesis and muscle mass, accompanied by a decrease in spermidine/spermine acetyltransferase 1 (Sat1). Denervation, resulted increased mTORC1 signalling and protein synthesis, and decreased muscle mass, which was associated with an increase in SpdSyn, spermine synthase (SpmSyn) and c-Myc. Combined, these data show that polyamine pathway enzymes are differentially regulated in models of altered mechanical and metabolic stress, and that Amd1 and SpdSyn are, in part, regulated in a mTORC1-dependent manner. Furthermore, these data suggest that polyamines may play a role in the adaptive response to stressors in skeletal muscle.
Figure: see text
T.B.R. Westgate, a Canadian Anglican priest who administered his church’s national system of Indian residential schools from 1921 to 1943, developed a sophisticated and effective ...bureaucracy to operate them efficiently, economically, and in compliance with government standards. He entirely supported the schools’ goal of Indigenous erasure, which accorded with his settler colonial outlook, his theological position, and his overseas missionary experience. All his decisions were framed by the need to make do with funding that was very limited since neither the government nor the settler church put much value on educating a people that they disparaged and expected to disappear. In his role, Westgate also functioned as the Anglican Church’s principal advocate for the assimilation of Indigenous Peoples into settler culture. His efforts, rationales, and failures are evaluated with reference to some of the insights of settler colonial studies.
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