The use of fasting and glycogen depletion to enhance skeletal muscle adaptation to training

Transcription

1 The use of fasting and glycogen depletion to enhance skeletal muscle adaptation to training Andrew Philp Ph.D. MRC-ARUK Centre for Musculoskeletal Ageing Research School of Sport, Exercise and Rehabilitation Sciences University of Birmingham, UK

2 Overview Molecular regulation of skeletal muscle to acute and chronic exercise Manipulating exercise responses to elicit enhanced training adaptation Training in the fasted state Training during glycogen depletion Discussion - Putting the theory into practice

3 Molecular adaptation to endurance training -Overview Systemic Protein/enzyme Gene (mrna) Egan and Zierath, (2013) Cell Metabolism. (17)

4 Connecting the dots: How does endurance exercise lead to skeletal muscle adaptation? Ca 2+ AMP NAD + ROS Energy sensing pathways Transcription co-regulators, transcription factors, nuclear receptors Fibre-type transformation Mitochondrial Biogenesis Vascularization SIGNAL: Muscle contraction alters the concentration of allosteric factors in skeletal muscle. SENSOR: Energy sensing proteins respond to alterations in these factors, initiating cellular metabolic processes. MEDIATOR: Energy sensing proteins target specific transcriptional regulators of metabolism, which in turn lead to altered fibretype characteristics, mitochondrial biogenesis and vascularization (angiogenesis).

5 Can manipulating substrate availability alter the exercise induced training response? Ca 2+ AMP NAD + ROS Energy sensing pathways NUTRITION: By using exercise and dietary interventions, can we manipulate the exercise stimulus or intracellular environment in favour of increased metabolic stress/adaptation Transcription co-regulators, transcription factors, nuclear receptors Fibre-type transformation Mitochondrial Biogenesis Vascularization

6 Strategy #1:The effect of fasting on metabolic responses to acute and chronic endurance exercise

7 FAST O/N Fast 178W Placebo CHO 722kcal 85% CHO 178W CHO 1g. kg/bw. hr 5g.kg/BW 9 healthy males (22 ±0.4yrs/BW 74.0 ±2.3 kg) De Bock et al (2005) J.Physiol (564)

8 Acute exercise in the fasted state led to substantial systemic metabolic alterations during and in recovery from exercise De Bock et al (2005) J.Physiol (564)

9 Acute exercise in the fasted state led to increased IMTG breakdown during exercise De Bock et al (2005) J.Physiol (564)

10 Acute exercise in the fasted state led to increased glycogen depletion during exercise but faster recovery post-exercise De Bock et al (2005) J.Physiol (564)

11 Acute exercise in the fasted state led to increased AMPK phosphorylation during exercise potential mechanism for altered metabolic regulation? De Bock et al (2005) J.Physiol (564)

12 Experimental trial: CHO 722kcal 85% CHO 178W CHO 1g. kg/bw. hr Training design (M/W/F 6 weeks): FASTED O/N Fast 178W Placebo FED 722kcal 178W CHO 1g. kg/bw. hr De Bock et al (2008) J. Appl. Physiol (104)

13 Exercise activation of genes involved in FFA transport and utilisation were increased to a greater extent in the fasted training exercise group De Bock et al (2008) J. Appl. Physiol (104)

14 Increased abundance of proteins involved in FFA and Glucose metabolism posttraining in the fasted exercise group. De Bock et al (2008) J. Appl. Physiol (104)

15 Potential mechanisms? AMPK as a metabolic sensor in skeletal muscle in response to fasting. De Lange et al (2007) FASEB. J (21)

16 General overview of proposed metabolic events in skeletal muscle following exercise in a fasted state. De Lange et al (2007) FASEB. J (21)

17 Strategy #1 -Summary Acute exercise in a fasted state (o/n fast and no CHO ingestion during exercise) leads to altered systemic responses to exercise and changes in IMTG breakdown and glycogen synthesis. Repeating this approach during training improves exerciseinduced increases in genes and proteins involved in FFA and glucose utilisation. AMPK (and other energy sensors) have been proposed as the mediators of the fasted training response. However the majority of this data has come from cell and rodents studies.

18 Strategy #2:The effect of glycogen depletion on metabolic responses to acute and chronic endurance exercise

19 S F Exercise to exhaustion results in rapid glycogen depletion, that is gradually restored over a 24h recovery period. The rate and magnitude of glycogen depletion is greater in type I muscle fibres. Casey et al (2007) J. Physiol (17)

20 Research question: Does performing exercise training in a glycogen depleted state alter skeletal muscle adaptation? Train low paradigm Hansen et al (2005) J. Appl. Physiol (98) 93-99

21 Training with low glycogen content (twice a day) increased mitochondrial enzyme activity without altering fibre-type characteristics Hansen et al (2005) J. Appl. Physiol (98) 93-99

22 Steady-state HIT Can this approach be applied to a real life training regime? Yeo et al (2008) J. Appl. Physiol (105)

23 Proof of concept - Muscle glycogen was significantly lower going into the HIT session in the LOW group compared to the HIGH training group. Yeo et al (2008) J. Appl. Physiol (105)

24 Following training the LOW group had significantly improved their ability to utilise FFA as a fuel during a steady-state exercise bout. Yeo et al (2008) J. Appl. Physiol (105)

25 Following training the LOW group had significant increases in metabolic enzyme activity and mitochondrial ETC protein content compared to the HIGH group. Yeo et al (2008) J. Appl. Physiol (105)

26 In a parallel study, the LOW training group significantly improved their ability to utilise IMTG stores as a fuel during a steady-state exercise bout. Hulston et al (2010) Med. Sci. Sports Exerc (42)

27 How might exercise in a glycogen depleted state lead to greater capacity to utilise FFA during exercise? Potential mechanisms? Philp et al (2012) AJP-Endocrinol. Metab (17)

28 Beginning to test this hypothesis Acute studies Clear glycogen depletion achieved in the LOW vs HIGH glycogen exercise groups Bartlett et al (2013) AJP Reg. Interg. Comp. Physiol (304) R450-R458

29 Enhanced transcriptional response of genes involved in mitochondrial remodelling in the LOW vs HIGH glycogen exercise group Bartlett et al (2013) AJP Reg. Interg. Comp. Physiol (304) R450-R458

30 Enhanced activity of AMPK (assessed via ACC phosphorylation) in the LOW vs HIGH glycogen exercise group Bartlett et al (2013) AJP Reg. Interg. Comp. Physiol (304) R450-R458

31 Strategy #2 -Summary Exercise training in a LOW glycogen state leads to greater increases in mitochondrial enzyme activity than HIGH training. Exercise training in a LOW glycogen state leads to improved rates of whole body fat oxidation and skeletal muscle IMTG utilisation during steady-state exercise. Exercise training in a LOW glycogen state leads to increased mitochondrial enzyme activity and abundance of mitochondrial ETC proteins. The activation of genes implicated in mitochondrial remodeling is greater following exercise in LOW glycogen.

32 So LOW = Enhanced training adaptation, but at what price? LOW glycogen group produced a significantly lower % of PPO during each HIT training session therefore LOW glycogen training should be used with caution... Yeo W K et al. J Appl Physiol 2008;105: Hulston et al (2010) Med. Sci. Sports Exerc (42)

33 Conclusions Clear similarities in acute and chronic adaptation to exercise in both fasted and glycogen depleted states. Altered CHO availability appears to promote skeletal muscle remodeling in favour of FFA utilisation. A number of molecular candidates have been proposed to mediate this response, but few proven in human skeletal muscle. The trade-off for reduced glycogen content is an impaired ability to perform at peak power outputs during HIT high intensity exercise. Therefore, LOW approaches should be periodisedwith HIGH training strategies to maximize training adaptation in relation to competitive performance.

34 Acknowledgements University of Birmingham (Philp Lab) Dr. Joaquin Perez-Schindler (Wellcome Trust) ZheSong (3 rd year PhD student) Mike McLeod (BBSRC) Jack Sargeant (MSc student) James East (MSc student) Collaborators Dr Simon Schenk (UCSD) Professor Rick Lieber (UCSD) Dr Keith Baar (UC Davis) Dr Lee Hamilton (Stirling University)