Exercise and rhabdomyolysis in long chain fa4y acid oxida5on disorders. Cary O. Harding, MD Molecular & Medical Gene5cs

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1 Exercise and rhabdomyolysis in long chain fa4y acid oxida5on disorders Cary O. Harding, MD Molecular & Medical Gene5cs

2 Acknowledgements OHSU Melanie Gillingham, PhD, RD Annie Behrend, MS, RD Autumn Fletcher, BS Julie Mar5n, MS, RD Diane Elliot, MD David Sahn, MD Mayo Laboratories Dieter Matern, MD, PhD St. Louis University James Shoemaker, MD, PhD University of WI- Madison Dale Schoeller, PhD

3 Case presenta5on 26 year old male former Marine Two year history of muscle cramps ater prolonged exercise Severe muscle pain while climbing Mt. St. Helens Unremarkable family history

4 Case presenta5on Serum crea5ne kinase = 65,000 units/l (normal < 200) Cola- colored urine Myoglobinuria Rhabdomyolysis

5 Exercise physiology

6 Energy balance Energy supply Energy demand

7

8 Mitochondrial FAO CPT-I translocase CPT-II Mitochondrial Membrane fatty acyl-coa O Very long-chain acyl-coa! Dehydrogenase (VLCAD) = R-CH 2 -CH 2 -C-S-CoA O = R-CH=CH-C-S-CoA Long-chain acylcarnitines! Trifunctional Protein Long-chain enoyl-coa! hydratase OH O Long-chain 3-hydroxy! acyl-coa dehydrogenase Long-chain 3-ketothiolase O R-C-S-CoA chain shortened acyl-coa = R-CH-CH 2 -C-S-CoA O O = R-C-CH 2 -C-S-CoA O CH 3 -C-S-CoA acetyl-coa Long-chain hydroxyacylcarnitines!

9 Normal muscle - H & E

10 Lessons from Aging!"#$%&'#()*+,& Sarcopenia = age- related loss of muscle mass & strength Loss of type II glycoly5c fibers Increased reliance on FAO in muscle with age -./*0&'#()*+,& DEF*&:&G&.8%H,&I,58$&& DEF*&@&G&H*5JE&I,58$8$%& 1*2*..3&4&*,&5.&46&7*#0".6&'+86&9:;<<=&<>?&@ABC@;B&& &

11 Respiratory exchange ra5o (RER) RER = CO 2 /O 2 RER of glucose = 1CO 2 /1O 2 = 1 RER of palmitate = 16CO 2 /23O 2 = 0.7 RER of res5ng muscle = 0.7

12 Treadmill ergometry Work VO 2 /kg Heart rate RQ 1.0 RQ 0.7 Lactate Time

13 Case 1 treadmill results RQ at rest = 0.9 During exercise, RQ > 1.0 at heart rate = bpm Impaired VO 2max /kg for age (25 ml/min/kg) Test terminated early due to fa5gue Postexercise lactate = 10 mm Postexercise CK = 2,000 units/l

14 Lipid storage myopathy

15 Trifunctional Protein! Long- Chain FAO Disorders Long-chain FA oxidation! Very long-chain acyl-coa! dehydrogenase! enoyl-coa hydratase! 3-hydroxyacyl-CoA! dehydrogenase! 3-ketothiolase! CPT-I! translocase! CPT-II! fatty acyl-coa! R-C-S-CoA chain shortened acyl-coa! R-CH2-CH2-C-S-CoA R-CH=CH-C-S-CoA OH R-CH-CH-C-S-CoA O! O! O! O! O! R-CH-CH-C-S-CoA O! O! Mitochondrial! Membrane! CH3-C-S-CoA acetyl-coa! Long- chain disorders with myopathy CPT2 VLCAD LCHAD/TFP Age of onset: childhood, adolescence, or adulthood Associated with illness, exercise or stress Advances with aging

16 LCFAOD exercise physiology TFP Control 30 V02/kg (ml/min/kg) Resting Early exercise Late exercise

17 LCFAOD exercise physiology TFP Control Respiratory quotient (RQ) Resting Early exercise Late exercise

18 LCFAOD exercise physiology 180 TFP Control 160 Heart rate (bpm) Resting Early exercise Late exercise

19 Moderate Intensity Exercise Randomized cross- over study 1 gm CHO per kg lean mass 0.5 gm MCT per kg lean mass Warm- up at 1.5 mile/hr X 3 min Increase speed and grade to maintain 60% max HR X 40 min 220- age (yrs) = es5mated max HR Repeat at same speed and grade Behrend, et al Molecular Gene5c & Metabolism 2012

20 Workload & VO 2 constant Factors affecting HR: 1. Biggest predictor = Workload (fixed) 2. O 2 need (Fick Principle) O 2 consumption = flow x AVO 2 dif 3. Ejection fraction (SV : EDV)

21 Decreased Glycoly5c Intermediates Blood samples before, ater and following HR recovery of exercise Analyzed for lactate, pyruvate, ketones by GC/MS MCT suppressed a) lactate and b) pyruvate concentra5ons before and ater exercise

22 Increased Ketone & Acetylcarni5ne Ketones & Acetylcarni5ne increased before & ater exercise Free fa4y acid rise similar between trt

23 Respiratory Exchange Ra5o RER lower with MCT Increased fa4y acid oxida5on Decreased carbohydrate oxida5on Difference observed at warm- up, 20 minutes ater MCT

24 Heart Rate Response Double Product : (estimate of myocardial O 2 consumption) DP = Systolic BP x HR Heart Rate significantly lower with MCT during workload No change in systolic blood pressure Double product lower with MCT ejection fraction AVO 2 difference

25 Treatment Op5ons for Myopathy Appropriate energy intake (BMR X 1.3 ac5vity) Increase protein intake to maintain muscle mass (20-25% energy with low- fat diet) Encourage exercise! MCT before moderate ac5vity (1-2 tsp MCT with CHO beverage 20 min before 45 min walking/cycling at MET 3-4) Strength training? Future treatment op5ons? Triheptanoin (enrolling Phase 2 Trial)

26 Triheptanoin Rhabdomyolysis occurs despite adequate energy Inability to fully oxidize acetyl- CoA provided by glucose or MCT oxida5on? Deple5on of CAC intermediates? Increase in lactate? C7 triglyceride provides source of propionyl- CoA to be converted to succinyl- CoA

27 Phase 2 Trial of Triheptanoin Treatment Baseline Assessment: Body composi5on Energy Expenditure In vivo FAO Cardiac func5on Exercise tolerance Randomized Parallel Design MCT 20% energy C7 20% energy 4 month treatment period 4- month Assessment: Body composi5on Energy Expenditure In vivo FAO Cardiac func5on Exercise tolerance Inclusion criteria: age 7-45 CPT2, VLCAD, LCHAD/TFP Ability to complete protocol Funded by FDA Office of Orphan Products Development R01FD03895

28 Thank You!