Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle

Thesis


Smiles, William J.. (2017). Autophagy and Protein Turnover Responses to Exercise-Nutrient Interactions in Human Skeletal Muscle [Thesis]. https://doi.org/10.4226/66/59f29efd01e38
AuthorsSmiles, William J.
Qualification nameDoctor of Philosophy (PhD)
Abstract

Skeletal muscle is a dynamic tissue comprising the largest protein reservoir of the human body with a rate of turnover of ~1-2% per day. Protein turnover is regulated by the coordination of intracellular systems regulating protein synthesis and breakdown that converge in a spatiotemporal manner on lysosomal organelles responsible for integrating a variety of contractile and nutritional stimuli. One such system, autophagy, which literally means to ‘self-eat,’ involves capturing of cellular material for deliver to, and disintegration by, the lysosome. The autophagic ‘cargo’ is subsequently recycled for use in synthetic reactions and thus maintenance of protein balance. As a dynamic system, autophagy responds to intracellular perturbations to homeostasis elicited by exercise and changes in nutrient availability in an attempt to restore energy balance. However, little is known regarding how autophagy is modulated following exercise in response to changes in nutrient availability. This thesis is comprised of three independent studies in which the effects of divergent forms of exercise-nutrient interactions are investigated in relation to autophagy-mediated protein turnover processes in skeletal muscle.

Study 1 assessed whether resistance-based exercise undertaken following a short-term period of dietary energy restriction activates autophagic cell signalling, and whether high-protein availability during recovery from exercise attenuates the autophagic response. This latter supposition was based on the anabolic properties of amino acids that may temporarily repress autophagy in vitro. In contrast to one of the original hypotheses, protein availability promoted the largest accumulation of proteins implicated in the induction of skeletal muscle autophagy and thus, turnover-remodelling, which is required to support the elevated synthetic demands imposed by resistance exercise contraction in a state of energy deficit.

Study 2 investigated the effects of alcohol intoxication during recovery from vigorous exercise on autophagy and whether concomitant protein availability could ‘rescue’ alcohol-exposed muscle tissue from the toxic effects of alcohol metabolism. It was hypothesised that the largest autophagic response (e.g., the accumulation of specific autophagy-related proteins in different subcellular compartments) would be seen when alcohol with carbohydrate, but not protein, was co-ingested, thereby promoting greater rates of protein degradation. However, the results from this study showed that alcohol availability consistently attenuated the abundance of numerous autophagy-related proteins that culminated in cell death responses. Protein availability, in part, through a compensatory induction of mitochondrial biogenesis, facilitated ‘sparing’ of the alcohol-exposed tissue from these deleterious effects of alcohol metabolism, thus revealing the intrinsic anti-apoptotic effects of exogenous protein. While excess alcohol consumption should be avoided following sport and/or exercise training, protein co-ingestion may relieve some of the intracellular damage and facilitate recovery-adaption.

Study 3 investigated the impact of acutely elevating systemic fatty acid availability and its impact on skeletal muscle protein turnover. Participants received either a lipid infusion with or without the addition of exercise, or a saline control, and following these infusions ingested a bolus amount of protein. It was hypothesised that lipid availability would attenuate markers of cellular anabolism (i.e., translation initiation) that would be ameliorated by exercise. Whereas the lipid infusion alone induced an elevated autophagic flux, combining the lipid infusion with exercise inhibited this activation of autophagy and, in response to protein ingestion, promoted the largest intracellular anabolic protein translational response. In addition, exercise performed during the lipid infusion resulted in a novel mitochondria-specific autophagic response independent of canonical routes of autophagic degradation. Therefore, the anabolic sensitivity of skeletal muscle to protein ingestion, despite high-circulating free fatty acids, was ‘rescued’ by strenuous exercise performed during this infusion and was associated with the disposal of mitochondrial organelles presumably damaged by lipid availability. Combining strenuous exercise with high-protein availability in the context of excess circulating lipids is a powerful stimulus for promoting muscle protein turnover-remodelling.

Taken collectively, the results from this thesis demonstrate that nutrient availability alters the responsiveness of skeletal muscle protein turnover, in particular autophagy, to exercise stimuli. The optimal nutrient ‘pairing’ with exercise in regards to optimising muscle quality and quantity for athletes and non-athletes alike, in the context of dietary energy restriction or excess alcohol and fat availability, is the consumption of high-quality sources of protein.

Keywordsautophagy; exercise; nutrient; protein; skeletal muscle
Year2017
PublisherACU Research Bank
Digital Object Identifier (DOI)https://doi.org/10.4226/66/59f29efd01e38
Research GroupMary MacKillop Institute for Health Research
Final version
Publication dates21 Jun 2017
Permalink -

https://acuresearchbank.acu.edu.au/item/8714x/autophagy-and-protein-turnover-responses-to-exercise-nutrient-interactions-in-human-skeletal-muscle

Download files

  • 17
    total views
  • 34
    total downloads
  • 0
    views this month
  • 2
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress
Ling, Naomi X. Y., Kaczmarek, Adrian, Hoque, Ashfaqul, Davie, Elizabeth, Ngoei, Kevin R. W., Morrison, Kaitlin R., Smiles, William J., Forte, Gabriella M., Wang, Tingting, Lie, Shervi, Dite, Toby A., Langendorf, Christopher G., Scott, John W., Oakhill, Jonathan S. and Petersen, Janni. (2020). mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress. Nature Metabolism. 2, pp. 41-49. https://doi.org/10.1038/s42255-019-0157-1
Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms
Stephen L. Pinkosky, John Scott, Eric M. Desjardins, Brennan Smith, Emily A. Day, Rebecca J. Ford, Christopher G. Langendorf, Naomi Ling, Tracy L. Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William Smiles, Kevin R. W. Ngoei, Michael W. Parker, Yan Yan, Karsten Melcher, Bruce Kemp, Jon Oakhill and Gregory R. Steinberg. (2020). Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms. Nature Metabolism. 2(9), pp. 873-881. https://doi.org/10.1038/s42255-020-0245-2
A single bout of strenuous exercise overcomes lipid-induced anabolic resistance to protein ingestion in overweight, middle-aged men
Smiles, William J., Churchward-Venne, Tyler A., van Loon, Luc J. C., Hawley, John A. and Camera, Donny M.. (2019). A single bout of strenuous exercise overcomes lipid-induced anabolic resistance to protein ingestion in overweight, middle-aged men. The FASEB Journal. 33(6), pp. 7009 - 7017. https://doi.org/10.1096/fj.201801917R
Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4
Ngoei, Kevin R.W., Langendorf, Christopher G., Ling, Naomi, Hoque, Ashfaqul, Johnson, Swapna, Camerino, Michelle C., Walker, Scott R., Bozikis, Ylva E., Dite, Toby A., Ovens, Ashley J., Smiles, William, Jacobs, Roxane, Huang, He, Parker, Michael W., Scott, John W., Rider, Mark H., Foitzik, Richard C., Kemp, Bruce, Baell, Jonathan B. and Oakhill, Jonathan S.. (2018). Structural determinants for small-molecule activation of skeletal muscle AMPK α2β2γ1 by the glucose importagog sc4. Cell Chemical Biology. 25(6), pp. 728 - 737. https://doi.org/10.1016/j.chembiol.2018.03.008
The guardian of the genome p53 regulates exercise-induced mitochondrial plasticity beyond organelle biogenesis
Smiles, William and Camera, Donny. (2018). The guardian of the genome p53 regulates exercise-induced mitochondrial plasticity beyond organelle biogenesis. Acta Physiologica. 222(3), pp. 1 - 13. https://doi.org/10.1111/apha.13004
Fenugreek increases insulin-stimulated creatine content in l6C11 muscle myotubes
Tomcik, Kristyen, Smiles, William, Camera, Donny, Hugel, Helmut M., Hawley, John and Watts, Rani. (2017). Fenugreek increases insulin-stimulated creatine content in l6C11 muscle myotubes. European Journal of Nutrition. 56(3), pp. 973 - 979. https://doi.org/10.1007/s00394-015-1145-1
Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise
Smiles, William, Conceição, Miguel S., Telles, Guilherme D., Chacon-Mikahil, Mara P.T., Cavaglieri, Cláudia R., Vechin, Felipe C., Libardi, Cleiton A., Hawley, John and Camera, Donny. (2017). Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise. European Journal of Applied Physiology. 117(2), pp. 345 - 358. https://doi.org/10.1007/s00421-016-3530-8
Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise
Camera, Donny, Burniston, Jatin G., Pogson, Mark A., Smiles, William and Hawley, John. (2017). Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise. The FASEB Journal. 31(12), pp. 5478 - 5494. https://doi.org/10.1096/fj.201700531R
Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans
Laker, R. C., Garde, C., Camera, Donny, Smiles, William, Zierath, J. R., Hawley, John and Barrès, R.. (2017). Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Scientific Reports. 7(1), pp. 1 - 12. https://doi.org/10.1038/s41598-017-15420-7
Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle
Tachtsis, Bill, Smiles, William, Lane, Steven C., Hawley, John Alan and Camera, Donny Michael. (2016). Acute endurance exercise induces nuclear p53 abundance in human skeletal muscle. Frontiers in Physiology. 7(144), pp. 1 - 10. https://doi.org/10.3389/fphys.2016.00144
Exercise-induced skeletal muscle signaling pathways and human athletic performance
Camera, Donny Michael, Smiles, William J. and Hawley, John Alan. (2016). Exercise-induced skeletal muscle signaling pathways and human athletic performance. Free Radical Biology & Medicine. 98, pp. 131 - 143. https://doi.org/10.1016/j.freeradbiomed.2016.02.007
Effects of skeletal muscle energy availability on protein turnover responses to exercise
Smiles, William J., Hawley, John Alan and Camera, Donny Michael. (2016). Effects of skeletal muscle energy availability on protein turnover responses to exercise. Journal of Experimental Biology. 219(Pt 2), pp. 214 - 225. https://doi.org/10.1242/jeb.125104
Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy
Smiles, William J., Parr, Evelyn B., Coffey, Vernon G., Lacham-Kaplan, Orly, Hawley, John Alan and Camera, Donny Michael. (2016). Protein coingestion with alcohol following strenuous exercise attenuates alcohol-induced intramyocellular apoptosis and inhibition of autophagy. American Journal of Physiology - Endocrinology and Metabolism. 311(5), pp. E836 - E849. https://doi.org/10.1152/ajpendo.00303.2016
The relationship between exercise, nutrition and type 2 diabetes
Stephenson, Erin J., Smiles, William and Hawley, John Alan. (2014). The relationship between exercise, nutrition and type 2 diabetes. Medicine and Sport Science. 60, pp. 1 - 10. https://doi.org/10.1159/000357331