Does Pharmacological Exercise Mimetics Exist? Hokkaido University Graduate School of Medicine Shintaro Kinugawa

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1 Does Pharmacological Exercise Mimetics Exist? Hokkaido University Graduate School of Medicine Shintaro Kinugawa

2 Survival rate (%) Peak oxygen uptake and prognosis in patients with heart failure (HF) 1 75 Peak Oxygen Uptake (VO 2 ) (ml/kg/min) >18 >14 18 > Follow up (Months) Mancini DM, et al. Circulation 1991; 83:

3 Factors regulating exercise capacity Peripheral circulation Pulmonary circulation Mitochondria CO 2 production Skeletal muscle O 2 consumption O 2 transport Heart Blood CO 2 transport Expiration Lung Inspiration VCO 2 VO 2 Small Reserve capacity Large

4 VO 2 (ml/min) Lactate (mg/dl) Leg blood flow (L/min) O 2 extraction (%) Dobutamine does not increase exercise capacity Control Dobutamine Rest Submax Max Rest Submax Max Rest Submax Max Rest Submax Max Wilson JR, et al. Am J Cardiol. 1984; 53:

5 Skeletal muscle abnormalities in HF Morphology Histology Biochemistry Others Muscle wasting Muscle fiber atrophy (IIb) Type I fibers Type II fibers Shift from type IIa to IIb Oxidative enzymes Glycolytic enzymes Impaired energy metabolism Ergoreflex Capillary density Shift from MHC1 to MHC2 Mitochondrial volume enos Apoptosis Skeletal muscle abnormalities are largely associated with the limited exercise capacity in patients with HF and are the target of exercise therapy. Okita K, et al. Circ J 213; 77: 293-3

6 Survival rate (%) Aerobic exercise training improves survival rate in patients with HF (ExTraMATCH) 1 9 Training Control Follow up (days) Modified, Piepoli MF. BMJ 24; 328: 189

7 Effects of exercise therapy for heart failure 1. Improve exercise capacity (peak VO 2, AT) 2. Minor change in cardiac function (LV systolic function and remodeling) 3. Improve endothelial function (Coronary and peripheral circulation) 4. Improve ventilation 5. Improve autonomic nerves function 6. Improve skeletal muscle abnormalities The greatest effect is to improve skeletal muscle abnormalities.

8 Treatment targeting skeletal muscle abnormalities Skeletal muscle abnormalities play an important role in the pathogenesis of HF. However, no therapy targeting skeletal muscle abnormalities has been developed. Developing new drug therapy may be useful for treatment of patients with severe HF who can t perform aerobic exercise. We focused on myokine secreted from skeletal muscle and performed studies.

9 Skeletal muscle is a huge endocrine organ Pedersen BK, et al. Nat Rev Endocrinol 212; 8:

Mass spectrometry Name Without caffeine Cover (%) MASCOT score Name With caffeine Cover (%) MASCOT

10 Search for proteins secreted by skeletal muscle contraction Caffeine (skeletal muscle contraction) Medium MW kda Silver stain C2C12 myotubes (mouse skeletal muscle) Cultured medium 15 Mass spectrometry Name Without caffeine Cover (%) MASCOT score Name With caffeine Cover (%) MASCOT score 1 MIF MIF VEGF 6 38 VEGF SPARC 5 36 BDNF 8 71 MWM Control Caffeine FSTL 3 44 FSTL 3 3

11 BDNF/total protein (Ratio to gastro) BDNF is preferentially present in the slow twitch fiber Gastro Soleus BDNF BDNF Soleus CBB staining Gastrocnemius Gastro Soleus SDH BDNF Type II Type I Type II Type I

12 Signal regulating mitochondrial biogenesis BDNF BDNF KO mice TrKBR CaMKK AMP ATP NAD + NADH NO CaMK AMPKα SIRT1 ROS Transcription PGC1α p38mapk Nucleus Electron transport chain Mitochondrion β-oxidation β-had Acetyl-CoA TCA cycle SIRT3 NAD + FAD ADP+Pi NADH FADH 2 ATP CO 2 NADH NAD + I II III Cyt c IV H + H + H + ADP +Pi F V F 1 ATP Intermembrane space Matrix Kinugawa et al. Int Heart J 215; 56:475-84

1 5 ET+ 8 7 6 5 4 3 2 1 ET+ 25 2 15 1 5 ET+ 18 17 16 15

13 Work (J) Run distance (m) Run time (sec) Peak VO 2 (ml/kg/min) BDNF mimics exercise training ET ET ET ET+ + = What a wonderful thing if this happen!!

14 P-AMPK/AMPK PGC-1/GAPDH mtdna (Ratio to ) Signaling regulating mitochondrial function p-ampk AMPK PGC-1 GAPDH ET+. ET+. ET+ p-ampk BDNF Exercise Training Mitochondrial function Exercise capacity

Work, J Peak VO 2, ml/kg/min BDNF/GAPDH P-AMPK/AMPK CS activity (mm/min/mg protein) Effects of AMPK activator in BDNF KO mice BDNF GAPDH 1..8.6 P-AMPK AMPK 1..8.6 25 2 15.4.4 1.2.2 5.

15 Work, J Peak VO 2, ml/kg/min BDNF/GAPDH P-AMPK/AMPK CS activity (mm/min/mg protein) Effects of AMPK activator in BDNF KO mice BDNF GAPDH P-AMPK AMPK WT BDNF KOBDNF KO +AICAR. WT BDNF KOBDNF KO +AICAR WT BDNF KOBDNF KO +AICAR WT BDNF KOBDNF KO +AICAR 1 WT BDNF KOBDNF KO +AICAR BDNF KO mice + AICAR(AMPK activator) p-ampk Mitochondrial function Exercise capacity

16 BDNF/GAPDH Serum BDNF (ng/ml) BDNF expression is decreased in the skeletal muscle from mice with HF after myocardial infarction Ope Observation 2wk Intervention 4wk 12 1 Sham 8 6 MI 4 2 n.d. n.d. BDNF rhbdn F GAPDH.4.2 Matsumoto J, et al. Circulation 218; 138:264-6

17 Peak VO 2 (ml/kg/min) Total running time (min) Lactate/work (mmol/l/j) Physical activity (count/day) Total running distance (m) Total work (J) BDNF improves exercise capacity in HF mice NS Matsumoto J, et al. Circulation 218; 138:264-6

18 pampkα/ampkα PGC1α/GAPDH BDNF activates AMPKα-PGC1α signal in the skeletal muscle pampkα AMPKα PGC1α GAPDH

19 O 2 flux (ratio to CI+II ETS ) BDNF improves mitochondrial respiration in the skeletal muscle P=.8 P=.13. CI Leak CI OXPHOS CI+II OXPHOS CI+II ETS CII ETS Matsumoto J, et al. Circulation 218; 138:264-6

20 Serum BDNF (ng/ml) Serum BDNF (ng/ml) BDNF and exercise capacity in patients with HF 4 P<.1 4 r=.53, P<.1 Control 3 3 HF Control HF Peak VO 2 (ml/kg/min) Fukushima A, et al. Int J Cardiol 213; 168: e142-4

21 Event-free rate BDNF is an independent predictor for clinical events BDNF 17.4 ng/ml (n=37).4.2 Log-rank test P=.1 BDNF<17.4 ng/ml (n=21) Months Fukushima A, et al. J Cardiac Fail 215; 21: 3-6

22 Conclusion BDNF may be a new treatment aiming at improvement in exercise capacity and targeting skeletal muscle.

Exercise Intolerance in Heart Failure: Significance of Skeletal Muscle Abnormalities

Exercise Intolerance in Heart Failure: Significance of Skeletal Muscle Abnormalities Hokkaido University Graduate School of Medicine Shintaro Kinugawa Survival rate (%) Peak oxygen uptake and prognosis