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1.
Metabolic protein kinase signalling in neuroblastoma.
Smiles, WJ, Catalano, L, Stefan, VE, Weber, DD, Kofler, B
Molecular metabolism. 2023;:101771
Abstract
BACKGROUND Neuroblastoma is a paediatric malignancy of incredibly complex aetiology. Oncogenic protein kinase signalling in neuroblastoma has conventionally focussed on transduction through the well-characterised PI3K/Akt and MAPK pathways, in which the latter has been implicated in treatment resistance. The discovery of the receptor tyrosine kinase ALK as a target of genetic alterations in cases of familial and sporadic neuroblastoma, was a breakthrough in the understanding of the complex genetic heterogeneity of neuroblastoma. However, despite progress in the development of small-molecule inhibitors of ALK, treatment resistance frequently arises and appears to be a feature of the disease. Moreover, since the identification of ALK, several additional protein kinases, including the PIM and Aurora kinases, have emerged not only as drivers of the disease phenotype, but also as promising druggable targets. This is particularly the case for Aurora-A, given its intimate engagement with MYCN, a driver oncogene of aggressive neuroblastoma previously considered 'undruggable.' SCOPE OF REVIEW Aided by significant advances in structural biology and a broader understanding of the mechanisms of protein kinase function and regulation, we comprehensively outline the role of protein kinase signalling, emphasising ALK, PIM and Aurora in neuroblastoma, their respective metabolic outputs, and broader implications for targeted therapies. MAJOR CONCLUSIONS Despite massively divergent regulatory mechanisms, ALK, PIM and Aurora kinases all obtain significant roles in cellular glycolytic and mitochondrial metabolism and neuroblastoma progression, and in several instances are implicated in treatment resistance. While metabolism of neuroblastoma tends to display hallmarks of the glycolytic "Warburg effect," aggressive, in particular MYCN-amplified tumours, retain functional mitochondrial metabolism, allowing for survival and proliferation under nutrient stress. Future strategies employing specific kinase inhibitors as part of the treatment regimen should consider combinatorial attempts at interfering with tumour metabolism, either through metabolic pathway inhibitors, or by dietary means, with a view to abolish metabolic flexibility that endows cancerous cells with a survival advantage.
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2.
Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.
Nay, K, Smiles, WJ, Kaiser, J, McAloon, LM, Loh, K, Galic, S, Oakhill, JS, Gundlach, AL, Scott, JW
International journal of molecular sciences. 2021;22(8)
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Exercise as therapy for mental health disorders has become common due to its reported benefits and low cost. There are many biological ways in which exercise may help mood disorders and diseases associated with brain degeneration and this review article aimed to highlight these. The authors first highlighted the research indicating that exercise may be protective in mood disorders with studies showing reduction of symptoms of depression, anxiety, schizophrenia, autism, and bipolar disorder. Exercise may also be of benefit in several brain degenerative disorders with studies indicating a positive impact in individuals with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis. Studies have also indicated that individuals with brain injuries, such as stroke may also benefit. Several reasons for this were highlighted. When muscle is stimulated during exercise a key brain signalling molecule may be produced, known as brain-derived neurotrophic factor (BDNF). BDNF may have the effect of preventing brain degeneration and promoting regeneration. Exercise may also increase gut microbial diversity and increase beneficial bacteria which may benefit the brain in several ways. It was concluded that exercise may have beneficial effects for individuals with brain disorders. This study could be used by healthcare professionals to understand how exercise may be of benefit to individuals with mood disorders, brain degenerative diseases and brain injuries as part of a holistic treatment plan.
Abstract
As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.
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3.
Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise.
Smiles, WJ, Conceição, MS, Telles, GD, Chacon-Mikahil, MP, Cavaglieri, CR, Vechin, FC, Libardi, CA, Hawley, JA, Camera, DM
European journal of applied physiology. 2017;(2):345-358
Abstract
PURPOSE Autophagy is an intracellular degradative system sensitive to hypoxia and exercise-induced perturbations to cellular bioenergetics. We determined the effects of low-intensity endurance-based exercise performed with blood-flow restriction (BFR) on cell signaling adaptive responses regulating autophagy and substrate metabolism in human skeletal muscle. METHODS In a randomized cross-over design, nine young, healthy but physically inactive males completed three experimental trials separated by 1 week of recovery consisting of either a resistance exercise bout (REX: 4 × 10 leg press repetitions, 70% 1-RM), endurance exercise (END: 30 min cycling, 70% VO2peak), or low-intensity cycling with BFR (15 min, 40% VO2peak). A resting muscle biopsy was obtained from the vastus lateralis 2 weeks prior to the first exercise trial and 3 h after each exercise bout. RESULTS END increased ULK1Ser757 phosphorylation above rest and BFR (~37 to 51%, P < 0.05). Following REX, there were significant elevations compared to rest (~348%) and BFR (~973%) for p38γ MAPKThr180/Tyr182 phosphorylation (P < 0.05). Parkin content was lower following BFR cycling compared to REX (~20%, P < 0.05). There were no exercise-induced changes in select markers of autophagy following BFR. Genes implicated in substrate metabolism (HK2 and PDK4) were increased above rest (~143 to 338%) and BFR cycling (~212 to 517%) with END (P < 0.001). CONCLUSION A single bout of low-intensity cycling with BFR is insufficient to induce intracellular "stress" responses (e.g., high rates of substrate turnover and local hypoxia) necessary to activate skeletal muscle autophagy signaling.
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Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise.
Camera, DM, Burniston, JG, Pogson, MA, Smiles, WJ, Hawley, JA
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017;(12):5478-5494
Abstract
It is generally accepted that muscle adaptation to resistance exercise (REX) training is underpinned by contraction-induced, increased rates of protein synthesis and dietary protein availability. By using dynamic proteome profiling (DPP), we investigated the contribution of both synthesis and breakdown to changes in abundance on a protein-by-protein basis in human skeletal muscle. Age-matched, overweight males consumed 9 d of a high-fat, low-carbohydrate diet during which time they either undertook 3 sessions of REX or performed no exercise. Precursor enrichment and the rate of incorporation of deuterium oxide into newly synthesized muscle proteins were determined by mass spectrometry. Ninety proteins were included in the DPP, with 28 proteins exhibiting significant responses to REX. The most common pattern of response was an increase in turnover, followed by an increase in abundance with no detectable increase in protein synthesis. Here, we provide novel evidence that demonstrates that the contribution of synthesis and breakdown to changes in protein abundance induced by REX differ on a protein-by-protein basis. We also highlight the importance of the degradation of individual muscle proteins after exercise in human skeletal muscle.-Camera, D. M., Burniston, J. G., Pogson, M. A., Smiles, W. J., Hawley, J. A. Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise.
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Exercise-induced skeletal muscle signaling pathways and human athletic performance.
Camera, DM, Smiles, WJ, Hawley, JA
Free radical biology & medicine. 2016;:131-143
Abstract
Skeletal muscle is a highly malleable tissue capable of altering its phenotype in response to external stimuli including exercise. This response is determined by the mode, (endurance- versus resistance-based), volume, intensity and frequency of exercise performed with the magnitude of this response-adaptation the basis for enhanced physical work capacity. However, training-induced adaptations in skeletal muscle are variable and unpredictable between individuals. With the recent application of molecular techniques to exercise biology, there has been a greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses. This review summarizes the molecular and cellular events mediating adaptation processes in skeletal muscle in response to exercise. We discuss established and novel cell signaling proteins mediating key physiological responses associated with enhanced exercise performance and the capacity for reactive oxygen and nitrogen species to modulate training adaptation responses. We also examine the molecular bases underpinning heterogeneous responses to resistance and endurance exercise and the dissociation between molecular 'markers' of training adaptation and subsequent exercise performance.
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Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy.
Smiles, WJ, Parr, EB, Coffey, VG, Lacham-Kaplan, O, Hawley, JA, Camera, DM
American journal of physiology. Endocrinology and metabolism. 2016;(5):E836-E849
Abstract
Alcohol ingestion decreases postexercise rates of muscle protein synthesis, but the mechanism(s) (e.g., increased protein breakdown) underlying this observation is unknown. Autophagy is an intracellular "recycling" system required for homeostatic substrate and organelle turnover; its dysregulation may provoke apoptosis and lead to muscle atrophy. We investigated the acute effects of alcohol ingestion on autophagic cell signaling responses to a bout of concurrent (combined resistance- and endurance-based) exercise. In a randomized crossover design, eight physically active males completed three experimental trials of concurrent exercise with either postexercise ingestion of alcohol and carbohydrate (12 ± 2 standard drinks; ALC-CHO), energy-matched alcohol and protein (ALC-PRO), or protein (PRO) only. Muscle biopsies were taken at rest and 2 and 8 h postexercise. Select autophagy-related gene (Atg) proteins decreased compared with rest with ALC-CHO (P < 0.05) but not ALC-PRO. There were parallel increases (P < 0.05) in p62 and PINK1 commensurate with a reduction in BNIP3 content, indicating a diminished capacity for mitochondria-specific autophagy (mitophagy) when alcohol and carbohydrate were coingested. DNA fragmentation increased in both alcohol conditions (P < 0.05); however, nuclear AIF accumulation preceded this apoptotic response with ALC-CHO only (P < 0.05). In contrast, increases in the nuclear content of p53, TFEB, and PGC-1α in ALC-PRO were accompanied by markers of mitochondrial biogenesis at the transcriptional (Tfam, SCO2, and NRF-1) and translational (COX-IV, ATPAF1, and VDAC1) level (P < 0.05). We conclude that alcohol ingestion following exercise triggers apoptosis, whereas the anabolic properties of protein coingestion may stimulate mitochondrial biogenesis to protect cellular homeostasis.
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7.
Modulation of autophagy signaling with resistance exercise and protein ingestion following short-term energy deficit.
Smiles, WJ, Areta, JL, Coffey, VG, Phillips, SM, Moore, DR, Stellingwerff, T, Burke, LM, Hawley, JA, Camera, DM
American journal of physiology. Regulatory, integrative and comparative physiology. 2015;(5):R603-12
Abstract
Autophagy contributes to remodeling of skeletal muscle and is sensitive to contractile activity and prevailing energy availability. We investigated changes in targeted genes and proteins with roles in autophagy following 5 days of energy balance (EB), energy deficit (ED), and resistance exercise (REX) after ED. Muscle biopsies from 15 subjects (8 males, 7 females) were taken at rest following 5 days of EB [45 kcal·kg fat free mass (FFM)(-1)·day(-1)] and 5 days of ED (30 kcal·kg FFM(-1)·day(-1)). After ED, subjects completed a bout of REX and consumed either placebo (PLA) or 30 g whey protein (PRO) immediately postexercise. Muscle biopsies were obtained at 1 and 4 h into recovery in each trial. Resting protein levels of autophagy-related gene protein 5 (Atg5) decreased after ED compared with EB (∼23%, P < 0.001) and remained below EB from 1 to 4 h postexercise in PLA (∼17%) and at 1 h in PRO (∼18%, P < 0.05). In addition, conjugated Atg5 (cAtg12) decreased below EB in PLA at 4 h (∼20, P < 0.05); however, its values were increased above this time point in PRO at 4 h alongside increases in FOXO1 above EB (∼22-26%, P < 0.05). Notably, these changes were subsequent to increases in unc-51-like kinase 1(Ser757) phosphorylation (∼60%) 1 h postexercise in PRO. No significant changes in gene expression of selected autophagy markers were found, but EGR-1 increased above ED and EB in PLA (∼417-864%) and PRO (∼1,417-2,731%) trials 1 h postexercise (P < 0.001). Postexercise protein availability, compared with placebo, can selectively promote autophagic responses to REX in ED.