Akt 1 – Mediated Skeletal Muscle Growth Attenuates Cardiac Dysfunction and Remodeling After Experimental Myocardial Infarction

Background—It is appreciated that aerobic endurance exercise can attenuate unfavorable myocardial remodeling following myocardial infarction. In contrast, little is known about the effects of increasing skeletal muscle mass, typically achieved through resistance training, on this process. Here, we utilized transgenic (TG) mice that can induce the growth of functional skeletal muscle by switching Akt1 signaling in muscle fibers to assess the impact of glycolytic muscle growth on post-myocardial infarction cardiac remodeling. Methods and Results—Male-noninduced TG mice and their nontransgenic littermates (control) were subjected to left anterior coronary artery ligation. Two days after surgery, mice were provided doxycycline in their drinking water to activate Akt1 transgene expression in a skeletal muscle-specific manner. Myogenic Akt1 activation led to diminished left ventricular dilation and reduced contractile dysfunction compared with control mice. Improved cardiac function in Akt1 TG mice was coupled to diminished myocyte hypertrophy, decreased interstitial fibrosis, and increased capillary density. ELISA and protein array analyses demonstrated that serum levels of proangiogenic growth factors were upregulated in Akt1 TG mice compared with control mice. Cardiac eNOS was activated in Akt1 TG mice after myocardial infarction. The protective effect of skeletal muscle Akt activation on cardiac remodeling and systolic function was abolished by treatment with the eNOS inhibitor L-NAME. Conclusions—Akt1–mediated skeletal muscle growth attenuates cardiac remodeling after myocardial infarction and is associated with an increased capillary density in the heart. This improvement appears to be mediated by skeletal muscle to cardiac communication, leading to activation of eNOS-signaling in the heart. (Circ Heart Fail. 2012;5:116-125.)

[1]  A. Karlamangla,et al.  Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey. , 2011, The Journal of clinical endocrinology and metabolism.

[2]  M. LeWinter,et al.  Chronic heart failure reduces Akt phosphorylation in human skeletal muscle: relationship to muscle size and function. , 2011, Journal of applied physiology.

[3]  N. LeBrasseur,et al.  Metabolic benefits of resistance training and fast glycolytic skeletal muscle. , 2011, American journal of physiology. Endocrinology and metabolism.

[4]  Zhen Yan,et al.  Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. , 2011, Journal of applied physiology.

[5]  D. Duncker,et al.  Beneficial effects of exercise training after myocardial infarction require full eNOS expression. , 2010, Journal of molecular and cellular cardiology.

[6]  B. Spiegelman,et al.  Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging , 2009, Proceedings of the National Academy of Sciences.

[7]  D. Duncker,et al.  Prior exercise improves survival, infarct healing, and left ventricular function after myocardial infarction. , 2009, Journal of applied physiology.

[8]  O. Gavrilova,et al.  Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity , 2009, PloS one.

[9]  William T. Abraham,et al.  Focused Update : ACCF / AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults , 2013 .

[10]  K. Walsh Adipokines, myokines and cardiovascular disease. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[11]  N. LeBrasseur,et al.  Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. , 2008, Cell metabolism.

[12]  B. Pedersen,et al.  Role of myokines in exercise and metabolism. , 2007, Journal of applied physiology.

[13]  William L Haskell,et al.  Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. , 2007, Circulation.

[14]  S. Kihara,et al.  Adiponectin protects against the development of systolic dysfunction following myocardial infarction. , 2007, Journal of molecular and cellular cardiology.

[15]  K. Sipido,et al.  Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction , 2007, Circulation research.

[16]  I. Shiojima,et al.  Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. , 2006, Genes & development.

[17]  S. Anker,et al.  Muscle wasting in cardiac cachexia. , 2005, The international journal of biochemistry & cell biology.

[18]  I. Shiojima,et al.  Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. , 2005, The Journal of clinical investigation.

[19]  J. Babraj,et al.  Selective activation of AMPK‐PGC‐1α or PKB‐TSC2‐mTOR signaling can explain specific adaptive responses to endurance or resistance training‐like electrical muscle stimulation , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  D. Yekutieli,et al.  Prior exercise training improves the outcome of acute myocardial infarction in the rat. Heart structure, function, and gene expression. , 2005, Journal of the American College of Cardiology.

[21]  G. Yancopoulos,et al.  Conditional Activation of Akt in Adult Skeletal Muscle Induces Rapid Hypertrophy , 2004, Molecular and Cellular Biology.

[22]  J. Hawley,et al.  Open access, freely available online Primer Skeletal Muscle Fiber Type: Influence on Contractile and Metabolic Properties , 2022 .

[23]  Marco Sandri,et al.  Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy , 2004, Cell.

[24]  M. Piepoli,et al.  Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH) , 2004, BMJ : British Medical Journal.

[25]  P. Antin,et al.  Tetracycline-Inducible System for Regulation of Skeletal Muscle-Specific Gene Expression in Transgenic Mice , 2003, Transgenic Research.

[26]  M. Heiman,et al.  Evaluation of a quantitative magnetic resonance method for mouse whole body composition analysis. , 2004, Obesity research.

[27]  D. Williamson,et al.  Immediate Response of Mammalian Target of Rapamycin (mTOR)‐Mediated Signalling Following Acute Resistance Exercise in Rat Skeletal Muscle , 2003, The Journal of physiology.

[28]  N. Aihara,et al.  Exercise training without ventricular remodeling in patients with moderate to severe left ventricular dysfunction early after acute myocardial infarction. , 2003, International journal of cardiology.

[29]  Ø. Ellingsen,et al.  Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy. , 2002, Journal of applied physiology.

[30]  D. Mukhopadhyay,et al.  Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth , 2002, Molecular and Cellular Biology.

[31]  Godfrey L. Smith,et al.  Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction. , 2002, Cardiovascular research.

[32]  Xiao-Ping Yang,et al.  Effect of ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists on Endothelial NO Synthase Knockout Mice With Heart Failure , 2002, Hypertension.

[33]  P. Gallagher,et al.  Reduction in hybrid single muscle fiber proportions with resistance training in humans. , 2001, Journal of applied physiology.

[34]  G. Yancopoulos,et al.  Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo , 2001, Nature Cell Biology.

[35]  J. Isner,et al.  Therapeutic angiogenesis in critical limb and myocardial ischemia. , 2001, Journal of interventional cardiology.

[36]  K. Esser,et al.  Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. , 2001, Journal of applied physiology.

[37]  A. Rolnitzky,et al.  [Cardiac cachexia]. , 2000, Harefuah.

[38]  W. Sessa,et al.  Regulation of endothelium-derived nitric oxide production by the protein kinase Akt , 1999, Nature.

[39]  P. Huang,et al.  Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. , 1998, The Journal of clinical investigation.

[40]  M Gattone,et al.  Attenuation of unfavorable remodeling by exercise training in postinfarction patients with left ventricular dysfunction: results of the Exercise in Left Ventricular Dysfunction (ELVD) trial. , 1997, Circulation.

[41]  G. Dziekan,et al.  Effect of exercise training on myocardial remodeling in patients with reduced left ventricular function after myocardial infarction: application of magnetic resonance imaging. , 1997, Circulation.

[42]  P. Ponikowski,et al.  Wasting as independent risk factor for mortality in chronic heart failure , 1997, The Lancet.

[43]  F. Crea,et al.  Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: evidence of subclinical myogenic myopathy. , 1989, Journal of the American College of Cardiology.

[44]  A. H. Norris,et al.  Effect of muscle mass decrease on age-related BMR changes. , 1977, Journal of applied physiology: respiratory, environmental and exercise physiology.