Exercise is Medicine?

1. Exercise is Medicine? James D. Fluckey, PhD, Muscle Biology Laboratory Department of Health and Kinesiology Texas A&M University

2. Exercise is Medicine • Joint initiative by the American Medical Association and the American College of Sports Medicine (November 2007) to explore possibilities that Exercise is Medicine. • A former President of the American Medical Association (May 2008) is a local Scott & White Physician, J. James Rohack, MD, who is also a member of the Huffine’s Institute at TAMU.

3. Exercise is Medicine So what does this really mean? • It is readily more accepted that physical activity (i.e., exercise) is important to the health and well-being of individuals, as well as may lead to preventative interventions of a number of chronic diseases: • Type II Diabetes • Cancer • COPD • Reduced dependence with advancing age…

4. Exercise is Medicine The Mission: • To make physical activity and exercise a standard part of a global disease prevention and medical treatment paradigm. • Enhance awareness in the medical community • Make ‘level of physical activity’ an important element in the diagnosis • Include physical activity counseling From www.exerciseismedicine.org

5. The laboratory was founded in 1992 by Professor Robert B. Armstrong. • Mission Statement: to explore physiological processes (mechanisms) related to the control of muscle protein metabolism. • Aging, exercise, microgravity/disuse, and disease

6. On-going studies in the MBL • Effect of Exercise Training on Mechanisms of Cellular Muscle Growth • Aging and Mechanisms of Human Muscle Protein Synthesis • Exercise Countermeasures to Affect Musculoskeletal Mass during Periods of Microgravity • Effect of High Intensity Resistance Exercise on Muscle Protein Homeostasis with Type II Diabetes • Effect of Exercising Muscle on Breast Cancer: Evidence of a Chemotherapeutic Agent Released during Exercise

7. Exercise is Medicine Diabetes… • Type II diabetes is associated with a loss of insulin sensitivity, leading to higher blood sugar. • Obesity • Hypertension and poor blood circulation • Neuropathy and retinopathy • Initial Concept… • Impaired insulin sensitivity results from defective signaling somewhere between the insulin receptor to the translocation of glucose transporters on the surface membranes (i.e., the system is broken).

8. Glycolysis Glucose uptake: role of insulin Thong et al., Physiology 20: 271, 2005

9. INSULIN Fyn Nck SHC GRB2 GLUT4 SOS Flotillin IRS1 Crk Ras GTP CAP Rab4 PI3K GRB10 APS GLUT4Vesicle Raf IRS1/2 SHC PPtase1 c-CbI MEKs AktPKB Rac Insulin PKC JNK PDK mTOR Insulin P P P P P P P P P P P P P P P P P P P ERKs GlycogenSynthase BAD EAI EAI GSK3 p70S6K eIF4EBP FKHRL1 c-Jun EEF2K BAD c-Fos 14-3-3 eIF2B EEF2 eIF4 S6 2009 ProteinLounge.com Elk c-CbI Glucose C PIP2 PIP3 Lipid Raft InsulinReceptor GLUT4Translocation lnsulin Receptor Pathway PIP2 PIP3 ReceptorInternalization H+ Insulin Degradation& ReceptorDephosphorylation H+ ATP Citrate lyase EBS Translation Translation Anti-apoptosis Fatty AcidSynthesis GeneExpression TRE Gene Expression

10. Exercise is Medicine Diabetes… • Research: • Specific sites within the signaling cascade have been systematically assessed, and ‘corrections’ to these sites have not proven fruitful. • Paradigm shift: • Reduced insulin sensitivity is not due to the system being broken, but a coordinated attempt to prevent glucose transport. New thoughts are leading investigators to believe that insulin resistance is likely a result of the cell sensing too much energy and too little demand…

11. Exercise is Medicine Diabetes and Exercise • A single bout of Aerobic Exercise leads to transient improvements in glucose tolerance! (WashU, CMRC, ECU, MSU, AKI, etc.) • Individuals with impaired glucose tolerance can be normalized with acute exposure to moderate intensity aerobic exercise! • Mechanism: Is it improved insulin sensitivity, or storage availability? • Depending on the ‘camp’, there does not appear to be a pronounced ‘training effect’, or if there is, it is ‘very short-lived’.

12. Exercise is Medicine • Insulin resistant subjects underwent three glucose challenge tests, either in the control state, following cycling exercise or after caloric restriction comparable to the caloric restriction imposed during the exercise trial. Each challenge was separated by several weeks and performed in random order. Larsen et al., Diabetologia. 1997 Apr;40(4):447-53.

13. Exercise is Medicine Diabetes and Exercise • Moderate Resistance Exercise doesn’t impact glucose tolerance without exercise training! (CWR, BSU, CMRC, etc.) • Individuals with impaired glucose tolerance typically show improved insulin sensitivity when muscles grow! • Mechanism: Is it improved insulin sensitivity, or storage availability? • Depending on the ‘camp’, there does appear to be a ‘training effect’, but generally only when the exercise facilitated muscle growth (or a change in body composition).

14. In addition to the elevation of muscle mass, resistance exercise training may restore control over protein homeostasis, which ultimately leads to better metabolic control in the cell.

15. Exercise is Medicine The Bottom Line: Diabetes and Exercise • Exercise, no matter what type, is generally considered to be an effective therapy for individuals with glucose intolerance. • Benefits of aerobic training appear to be dependent on the last bout of exercise… • Benefits of resistance training appear to be dependent on the training response. • Although not completely understood, it appears as though the medicinal effect of exercise serves to maximize ‘flux’ through the metabolic system, improving control over glucose disposal.

16. Exercise is Medicine • Cancer and Exercise • An evolution of thoughts leading to our current experiments… • From glucoregulatory control to cancer killers! • Once upon a time… • Galbo lab (CMRC) conducted a series of studies attempting to understand HGO at the onset of exercise.

17. BLOOD GLUCOSE LEVELS and Exercise From Wilmore, J.H., and D.L. Costill. Physiology of Sport and Exercise. 3rd Edition, Champaign: Human Kinetics, 2004

18. Exercise is Medicine • HGO, in anticipation or response to exercise is a result of: • Sympathetic innervation of the liver, changes in hormone profiles allowing/stimulating release of glucose, etc… • CMRC performed interesting studies in liver transplant patients, leading us to suspect there may be other control features as well…

19. Muscle as an Endocrine Tissue? • When you account for all of these parameters (hormones, etc) in liver transplant patients (no neural input/output), hepatic glucose output is still elevated at the onset of exercise… • Galbo (CMRC): Clearly there are factors being released in response to exercise that affect HGO, and a logical source of these factors is skeletal muscle.

20. Muscle-born factors leading to HGO? • Experiments… • Phase 1. • In order to assess the possibility that muscle-born factors could be responsible for HGO at the onset of exercise, we conducted ‘parallel perfusion’ experiments and measured hepatic glucose output.

24. Parallel Perfusion Technique From Xiao Xia Han

25. Hepatic Glucose Output and Muscle Contractions

26. Muscle-born factors leading to HGO? • Experiments… • Phase 2. • In order to assess the possibility that muscle-born factors are resident in the myocyte (muscle tissue) prior to exercise, we used fractionated muscle homogenates (without prior exercise) that were dessicated, reconstituted and introduced to perfused livers.

27. Hepatic Glucose Output and Muscle Contractions

28. Communication: Can Muscle Talk Back? • There is direct evidence that substances released from exercising muscle can affect HGO, suggesting that this is an endocrine-like response. • Other indications that muscle may be able to communicate too… • Makes IGF-1, which is released in autocrine, paracrine or ‘hormone’ fashion • Also capable of making various cytokines, which may be released into the bloodstream (generalized response?) • Recently been shown that muscle makes factors such as brain-derived neurotrophic factor (BDNF) – but no systematic evidence that factors are indeed released, coordinated or regulated.

29. Muscle as an Endocrine Tissue? • Studies exploring the possibility of myokines have resulted in the isolation of some 400 different factors secreted by muscle. • Many of these myokines are released during physical activity, and may have a role in training-associated metabolic changes, immune system regulation, and more. • An aim of our lab is to determine what other effects may arise from the release of exercise-derived myokines…

30. Michelle Holmes, MD, PhD, of Harvard Medical School, and Brigham and Women’s Hospital JAMA (293: 2479–2486, 2005). • Women who exercised the equivalent of walking for ~1 hour a week, at a 2 to 3 mile-per-hour pace, had a lower risk of dying from breastcancer than women who got less than an hour’s worth of physical activity each week (20% reduction) • Women who did a little more than that—the equivalent of walking about 3 to 5 hours per week at that pace—had the lowest risk of dying (50% reduction)

31. Exercise and Cancer? The effect of exercise on cancer? • Most acknowledge that exercise can be an important therapy for individuals with cancer, but these benefits are thought to be of an ‘indirect’ nature. • The benefit of exercise may be of metabolic nature, since exercise affects whole-body metabolism (i.e. weight/fat loss, hormonal adaptations, altered metabolic rate, etc.) or psychological (i.e., mood state). • Little systematic evidence exists that exercise may have a ‘direct’ effect on cancer.

32. Speaking of Communication: Yep, yet another pathway! IRPA Studies (Intracollegiate Rat Powerlifters’ Association) Leonard (Jim) Jefferson Penn State Medical School Henrik Galbo (CMRC) Peter Farrell (Penn State – ECU) Matt Hickey (CSU – HPL) Xiao Xia Han (CMRC – U Copenhagen) HGO Experiments Bill Kraemer (CSM/PSU – Uconn) Scott Gordon (Penn State - ECU) G. Lynis Dohm (ECU Medical School) Bill Evans (Penn State – UAMS – GSK/Duke) Donna Korzick (Penn State) Sue Bloomfield (Texas &M University) Todd Trappe (UAMS – Ball State) UAMS – NSBRI Consortium Kim Westerlind (Mayo – UC-Denver HSC) Per Tesch (Karolinska – UAMS – UNS) Cancer Center Research (International Rat Powerlifters’ Association)

33. Exercise and Cancer • The purpose of the study was to determine if factors released from skeletal muscle were capable of exerting biological actions on specific cancer cell lines.

34. Female Wistar rats were hind limb perfused, and the perfusate passing through the hindlimb was collected and exposed to MCF7 cell lines. Methodology…

35. Female Wistar rats were hind limb perfused, and the perfusate passing through the hindlimb was collected and exposed to MCF7 cell lines. • Muscles were electrically stimulated to contract, perfusate collected, and exposed to MCF7 Cell lines.

36. Effect of exercise on cancer…

37. Methodology… • Collected perfusates with and without muscle contraction were processed and administered to tumor-bearing rats.

38. Effect of exercise on cancer…

39. Effect of exercise on cancer… • These data are the first to demonstrate a direct effect of factor(s) arising from contracting muscle on cancer cell lines. • There appears to be a specific effect on tumor cells, and may ultimately facilitate tumor-specific cell death by a yet to be identified mechanism. • We are now conducting experiments to isolate, characterize, and test through bioassay the specific myokine(s) exhibiting this chemotherapeutic action.

40. University of Colorado-Health Sciences Center Kim Caroline-Strange Rob Strange Texas A&M Steven Riechman, PhD HLKN/MBL PhD Students Amanda Davis* Michael Wiggs Heath Gasier Mats Nilsson Justin Dobson Kevin Shimkus Acknowledgements