Effect of myostatin deletion on cardiac and microvascular function

Joshua T Butcher, M Irfan Ali, Merry W Ma, Cameron G McCarthy, Bianca N Islam, Lauren G Fox, James D Mintz, Sebastian Larion, David J Fulton, David W Stepp, Joshua T Butcher, M Irfan Ali, Merry W Ma, Cameron G McCarthy, Bianca N Islam, Lauren G Fox, James D Mintz, Sebastian Larion, David J Fulton, David W Stepp

Abstract

The objective of this study is to test the hypothesis that increased muscle mass has positive effects on cardiovascular function. Specifically, we tested the hypothesis that increases in lean body mass caused by deletion of myostatin improves cardiac performance and vascular function. Echocardiography was used to quantify left ventricular function at baseline and after acute administration of propranolol and isoproterenol to assess β-adrenergic reactivity. Additionally, resistance vessels in several beds were removed, cannulated, pressurized to 60 mmHg and reactivity to vasoactive stimuli was assessed. Hemodynamics were measured using in vivo radiotelemetry. Myostatin deletion results in increased fractional shortening at baseline. Additionally, arterioles in the coronary and muscular microcirculations are more sensitive to endothelial-dependent dilation while nonmuscular beds or the aorta were unaffected. β-adrenergic dilation was increased in both coronary and conduit arteries, suggesting a systemic effect of increased muscle mass on vascular function. Overall hemodynamics and physical characteristics (heart weight and size) remained unchanged. Myostatin deletion mimics in part the effects of exercise on cardiovascular function. It significantly increases lean muscle mass and results in muscle-specific increases in endothelium-dependent vasodilation. This suggests that increases in muscle mass may serve as a buffer against pathological states that specifically target cardiac function (heart failure), the β-adrenergic system (age), and nitric oxide bio-availability (atherosclerosis). Taken together, pharmacological inhibition of the myostatin pathway could prove an excellent mechanism by which the benefits of exercise can be conferred in patients that are unable to exercise.

Keywords: Augmented muscle mass; cardiac function; coronary microvasculature; exercise; myostatin; nitric oxide; β‐adrenergic.

© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Figures

Figure 1
Figure 1
Baseline cardiac function is improved in myostatin KO mice. Ultrasound was used to examine baseline cardiac function in panels (A–D). End diastolic diameter (A) is unchanged between groups. End systolic diameter (B) is significantly reduced in the myostatin KO. Fractional shortening (C) is increased in the myostatin KO. Heart rate (D) is unchanged between the two groups. Panel (E & F) show myocyte characteristics. Myocyte size, assessed by cross sectional area (E) or perimeter (F) is unchanged between the two groups. N ≥ 7 and *P < 0.05 against control.
Figure 2
Figure 2
Effect of myostatin deletion on β‐adrenergic regulation of the heart. Ultrasound is used to examine β‐adrenergic adjustments to the heart. β‐blockade is accomplished using propranolol and β‐stimulation with isoproterenol. The increase in fractional shortening (A) and ejection fraction (B) at baseline is accompanied by parallel shifts down and up with β‐blockade and or antagonism, respectively, in each group. N ≥ 7 and *P < 0.05 against control.
Figure 3
Figure 3
Comparison of endothelial modulation of vascular function. Myostatin KO mice have increased vasodilation to acetylcholine compared to control mice and this increase can be abolished with L‐NAME (A). Smooth muscle function, as assessed by SNP (B) or endothelin‐1 (C) was unchanged between the two groups. N ≥ 5 and *P < 0.05 against control.
Figure 4
Figure 4
Further comparison of endothelial modulation of vascular function. Myostatin KO mice also have an increased vasodilatory response to isoproterenol (A). A dose– response curve to papaverine (B) shows no difference between the groups. Aortic reactivity to isoproterenol (C) shows a significant increase in dilation in the myostatin KO mouse and is blunted in the presence of L‐NAME. N ≥ 5 and *P < 0.05 against matched treatment control.
Figure 5
Figure 5
Myostatin deletion increases endothelial sensitivity in skeletal muscle resistance vasculature. Dose–response curves to acetylcholine in four different vascular beds are shown in Figure 5. Myostatin KO skeletal muscle vasculature (A) show a significant dilation in the myostatin KO mice compared to control. Gonadal arterioles (B) show no difference between the groups. Mesenteric arterioles (C) have a significantly blunted vasodilator response in the myostatin KO mice. The aorta (D) has no significant difference between the groups. N ≥ 8 for Panel A and N ≥ 3 for Panel B and C. *P < 0.05 against control.
Figure 6
Figure 6
Myostatin deletion does not alter blood pressure or heart rate. Blood pressure (A),heart rate (B), systolic (C) and diastolic pressure (D) averaged over 7 days are unchanged between groups. N ≥ 5 and *P < 0.05 against control.

References

    1. Adams, V. , Reich B., Uhlemann M., and Niebauer J.. 2017. Molecular effects of exercise training in patients with cardiovascular disease: Focus on skeletal muscle, endothelium, and myocardium. Am. J. Physiol. Heart Circ. Physiol. 313:H72–H88.
    1. Arem, H. , Moore S. C., Patel A., Hartge P., Berrington de Gonzalez A., Visvanathan K., et al. 2015. Leisure time physical activity and mortality: a detailed pooled analysis of the dose‐response relationship. JAMA Intern. Med. 175:959–967.
    1. Camporez, J. P. , Petersen M. C., Abudukadier A., Moreira G. V., Jurczak M. J., Friedman G., et al. 2016. Anti‐myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc. Natl Acad. Sci. USA 113:2212–2217.
    1. Carlson, S. A. , Fulton J. E., Pratt M., Yang Z., and Adams E. K.. 2015. Inadequate physical activity and health care expenditures in the United States. Prog. Cardiovasc. Dis. 57:315–323.
    1. Cornelissen, V. A. , and Fagard R. H.. 2005. Effects of endurance training on blood pressure, blood pressure‐regulating mechanisms, and cardiovascular risk factors. Hypertension 46:667–675.
    1. Cornelissen, V. A. , Fagard R. H., Coeckelberghs E., and Vanhees L.. 2011. Impact of resistance training on blood pressure and other cardiovascular risk factors: a meta‐analysis of randomized, controlled trials. Hypertension 58:950–958.
    1. Dengel, D. R. , et al. 1985. Distinct effects of aerobic exercise training and weight loss on glucose homeostasis in obese sedentary men. J. Appl. Physiol. 1996:318–325.
    1. Dimeo, F. , Pagonas N., Seibert F., Arndt R., Zidek W., and Westhoff T. H.. 2012. Aerobic exercise reduces blood pressure in resistant hypertension. Hypertension 60:653–658.
    1. Dutheil, F. , Lac G., Lesourd B., Chapier R., Walther G., Vinet A., et al. 2013. Different modalities of exercise to reduce visceral fat mass and cardiovascular risk in metabolic syndrome: the RESOLVE* randomized trial. Int. J. Cardiol. 168:3634–3642.
    1. Ehsani, A. A. , Ogawa T., Miller T. R., Spina R. J., and Jilka S. M.. 1991. Exercise training improves left ventricular systolic function in older men. Circulation 83:96–103.
    1. Gebel, K. , Ding D., Chey T., Stamatakis E., Brown W. J., and Bauman A. E.. 2015. Effect of moderate to vigorous physical activity on all‐cause mortality in middle‐aged and older Australians. JAMA Intern. Med. 175:970–977.
    1. Gonzalez‐Cadavid, N. F. , Taylor W. E., Yarasheski K., Sinha‐Hikim I., Ma K., Ezzat S., et al. 1998. Organization of the human myostatin gene and expression in healthy men and HIV‐infected men with muscle wasting. Proc Natl Acad Sci U S A 95:14938–43.
    1. Green, D. J. , Hopman M. T., Padilla J., Laughlin M. H., and Thijssen D. H.. 2017. Vascular adaptation to exercise in humans: role of hemodynamic stimuli. Physiol. Rev. 97:495–528.
    1. Hambrecht, R. , Wolf A., Gielen S., Linke A., Hofer J., Erbs S., et al. 2000. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N. Engl. J. Med. 342:454–460.
    1. Han, H. Q. , and Mitch W. E.. 2011. Targeting the myostatin signaling pathway to treat muscle wasting diseases. Curr. Opin. Support Palliat. Care 5:334–341.
    1. Hornig, B. , Maier V., and Drexler H.. 1996. Physical training improves endothelial function in patients with chronic heart failure. Circulation 93:210–214.
    1. Koller, A. , Huang A., Sun D., and Kaley G.. 1995. Exercise training augments flow‐dependent dilation in rat skeletal muscle arterioles. Role of endothelial nitric oxide and prostaglandins. Circ. Res. 76:544–550.
    1. Kraus, W. E. , Houmard J. A., Duscha B. D., Knetzger K. J., Wharton M. B., McCartney J. S., et al. 2002. Effects of the amount and intensity of exercise on plasma lipoproteins. N. Engl. J. Med. 347:1483–1492.
    1. Latres, E. , Pangilinan J., Miloscio L., Bauerlein R., Na E., Potocky T. B., et al. 2015. Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice. Skelet Muscle 5:34.
    1. Lee, S. J. , and McPherron A. C.. 2001. Regulation of myostatin activity and muscle growth. Proc. Natl Acad. Sci. USA 98:9306–9311.
    1. Lee, I. M. , Shiroma E. J., Lobelo F., Puska P., Blair S. N., and Katzmarzyk P. T.. 2012. Effect of physical inactivity on major non‐communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380:219–229.
    1. Matsakas, A. , and Diel P.. 2005. The growth factor myostatin, a key regulator in skeletal muscle growth and homeostasis. Int. J. Sports Med. 26:83–89.
    1. Matsakas, A. , Macharia R., Otto A., Elashry M. I., Mouisel E., Romanello V., et al. 2012. Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse. Exp. Physiol. 97:125–140.
    1. McMullan, R. C. , Kelly S. A., Hua K., Buckley B. K., Faber J. E., de Villena F. P., et al. 2016. Long‐term exercise in mice has sex‐dependent benefits on body composition and metabolism during aging. Physiol. Rep. 4:e13011.
    1. Morissette, M. R. , Stricker J. C., Rosenberg M. A., Buranasombati C., Levitan E. B., Mittleman M. A., et al. 2009. Effects of myostatin deletion in aging mice. Aging Cell 8:573–583.
    1. Myers, J. 2003. Cardiology patient pages. Exercise and cardiovascular health. Circulation 107:e2–e5.
    1. Newcomer, S. C. , Thijssen D. H., and Green D. J.. 2011. Effects of exercise on endothelium and endothelium/smooth muscle cross talk: role of exercise‐induced hemodynamics. J. Appl. Physiol. 1985 57:311–320.
    1. Niebauer, J. , and Cooke J. P.. 1996. Cardiovascular effects of exercise: role of endothelial shear stress. J. Am. Coll. Cardiol. 28:1652–1660.
    1. Nillni, E. A. 2010. Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front. Neuroendocrinol. 31:134–156.
    1. Parker, R. J. , Berkowitz B. A., Lee C. H., and Denckla W. D.. 1978. Vascular relaxation, aging and thyroid hormones. Mech. Ageing Dev. 8:397–405.
    1. Patel, K. , and Amthor H.. 2005. The function of Myostatin and strategies of Myostatin blockade‐new hope for therapies aimed at promoting growth of skeletal muscle. Neuromuscul. Disord. 15:117–126.
    1. Phillips, S. A. , Mahmoud A. M., Brown M. D., and Haus J. M.. 2015. Exercise interventions and peripheral arterial function: implications for cardio‐metabolic disease. Prog. Cardiovasc. Dis. 57:521–534.
    1. Qiu, S. , Mintz J. D., Salet C. D., Han W., Giannis A., Chen F., et al. 2014. Increasing muscle mass improves vascular function in obese (db/db) mice. J. Am. Heart Assoc. 3:e000854.
    1. Reardon, K. A. , Davis J., Kapsa R. M., Choong P., and Byrne E.. 2001. Myostatin, insulin‐like growth factor‐1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy. Muscle Nerve 24:893–899.
    1. Reisz‐Porszasz, S. , Bhasin S., Artaza J. N., Shen R., Sinha‐Hikim I., Hogue A., et al. 2003. Lower skeletal muscle mass in male transgenic mice with muscle‐specific overexpression of myostatin. Am. J. Physiol. Endocrinol. Metab. 285:E876–E888.
    1. Rodgers, B. D. , Interlichia J. P., Garikipati D. K., Mamidi R., Chandra M., Nelson O. L., et al. 2009. Myostatin represses physiological hypertrophy of the heart and excitation‐contraction coupling. J. Physiol. 587(Pt 20):4873–4886.
    1. Ross, R. , Dagnone D., Jones P. J., Smith H., Paddags A., Hudson R., et al. 2000. Reduction in obesity and related comorbid conditions after diet‐induced weight loss or exercise‐induced weight loss in men. A randomized, controlled trial. Ann. Intern. Med. 133:92–103.
    1. Schuelke, M. , Wagner K. R., Stolz L. E., Hübner C., Riebel T., Kömen W., et al. 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350:2682–2688.
    1. Sessa, W. C. , Pritchard K., Seyedi N., Wang J., and Hintze T. H.. 1994. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ. Res. 74:349–353.
    1. Stepp, D. W. , Pollock D. M., and Frisbee J. C.. 2004. Low‐flow vascular remodeling in the metabolic syndrome X. Am. J. Physiol. Heart Circ. Physiol. 286:H964–H970.
    1. Stepp, D. W. , Osakwe C. C., de Chantemele E. J., and Mintz J. D.. 2013. Vascular effects of deletion of melanocortin‐4 receptors in rats. Physiol. Rep 1:e00146.
    1. Tsujimoto, G. , Hashimoto K., and Hoffman B. B.. 1987. Effects of thyroid hormone on beta‐adrenergic responsiveness of aging cardiovascular systems. Am. J. Physiol. 252(3 Pt 2):H513–H520.
    1. Wang, J. , Wolin M. S., and Hintze T. H.. 1993. Chronic exercise enhances endothelium‐mediated dilation of epicardial coronary artery in conscious dogs. Circ. Res. 73:829–838.
    1. Warburton, D. E. , Nicol C. W., and Bredin S. S.. 2006. Health benefits of physical activity: the evidence. CMAJ 174:801–809.
    1. Whittemore, L. A. , Song K., Li X., Aghajanian J., Davies M., Girgenrath S., et al. 2003. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem. Biophys. Res. Comm. 300:965–971.
    1. Yates, T. , Khunti K., Bull F., Gorely T., and Davies M. J.. 2007. The role of physical activity in the management of impaired glucose tolerance: a systematic review. Diabetologia 50:1116–1126.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe