Exercise-induced cardiac hypertrophy: Structural adaptation In the name of God Exercise-induced cardiac hypertrophy: Structural adaptation Hamid Agha Alinejad,PhD Hamid Agha Alinejad Tarbiat Modares University

Introduction Hamid Agha Alinejad Cardiac hypertrophy refers to the growth process of the cardiomyocytes (CM), and thus to the cardiac thickening and remodeling. This process may be due to a cardiac pathology or to a long-term exercise training Agha Alinejad H.

Pathological cardiac hypertrophy; Hamid Agha Alinejad Pathological cardiac hypertrophy; a compensatory mechanism for maintaining cardiac function. Is characterized by; the growth of myocardial fibers changes in cardiac architecture change in cellular metabolism myocardial fibrosis myocardial dysfunction increased morbidity and mortality (Florescu & Vinereanu, 2006).

Pathologic hypertrophy Hamid Agha Alinejad Pathologic hypertrophy

Pathologic hypertrophy due to: Hamid Agha Alinejad Pathologic hypertrophy due to: Chronic pressure overload (e.g. systemic hypertension, aortic stenosis) Volume overload (e.g. aortic regurgitation), or myocardial disease (e.g. hypertrophic cardiomyopathy (Perrino et al., 2006).

Physiologic cardiac hypertrophy; Hamid Agha Alinejad Physiologic cardiac hypertrophy; in order to response to the specific haemodynamic requirements. Is characterized by; preserved myocardial structure normal pattern of gene expression normal metabolism not progress to left ventricular dysfunction (Rajiv et al., 2004).

Morphologic forms of physiologic hypertrophy Hamid Agha Alinejad Two morphological forms of physiologic hypertrophy; An endurance-trained heart present in athletes involved in sports with a high dynamic component. A strength-trained heart present in athletes involved mainly in isometric exercise

During endurance training; Hamid Agha Alinejad During endurance training; Volume overload occurs (cardiac output can increase up to 40 l/min) Causing eccentric hypertrophy – increase of left ventricular internal diameter, with a moderate increase of the wall thickness.

During strength training; Hamid Agha Alinejad During strength training; Pressure overload occurs(up to 48/35cmHg) Inducing concentric hypertrophy – thickening of the ventricular wall, with unchanged cavity diameter.

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The ventricular septum of an elite male rower Hamid Agha Alinejad The ventricular septum of an elite male rower At the peak of athletic conditioning After an 8 week deconditioning

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Molecular & cellular basis of cardiac hypertrophy Hamid Agha Alinejad Molecular & cellular basis of cardiac hypertrophy Exercise training induces physiologic hypertrophy - adaptive cardiac myocyte (CM) growth- with increased or neutral function.

Hamid Agha Alinejad There is a time dependent increase in CM mass & cell size due to exercise training.

Hypertrophic response to exercise training in CMs is due; Hamid Agha Alinejad Hypertrophic response to exercise training in CMs is due; growth factors transcription factors regulating factors in compensatory phases of pressure & volume overload (McMullen et al., 2003; Wilkins et al.,2004; O’Connell et al.,2003).

Five stimuli for adaptive changes in the CMs: Hamid Agha Alinejad Five stimuli for adaptive changes in the CMs: 1-External humoral factors such as hormones, peptide growth factors & neurotransmitters; 2-Mechanical loads; 3- Change in intracellular calcium concentration related to contractile activity; 4- Hypoxia; 5- Cellular redox state.

Exercise- induced endocrine factors Hamid Agha Alinejad Exercise- induced endocrine factors Exercise with different intensity → biological stress → different downstream effects such as gene regulation.

Renin-Angiotensin-Aldostrone pressure overload & congestive heart failure →↑ Angiotensin II → Stimulation of G-protein receptors → phosphorilation of IP3 → act. calcineurin → NFAT → hypertrophic response genes Hamid Agha Alinejad Agha Alinejad H.

Endurance activities → ↑ sympathetic nerve Hamid Agha Alinejad Endurance activities → ↑ sympathetic nerve activity → ↓ renal blood flow → renin secretion → ↑ angiotensin & aldostrone during & immediately after exercise But, its long-term effects of training remains to be determined.

GH & IGF-1 IGF-1 initiate autophosphorylation of insulin receptor substrate (IRS-1) & PI3-kinase (PI3K). Hamid Agha Alinejad

Hamid Agha Alinejad Cytokines IL-1, LIF, TNF- α & CT-1 may include or modulate growth in CMs (Chien 2004). Their significance in exercise-induced hypertrophy has not been established. CT-1 induce a hypertrophic phenotype of elongated CMs with minimal change in cell width.

Mechanical stress In pathologic hypertrophy; Hamid Agha Alinejad Mechanical stress In pathologic hypertrophy; In pressure overload by aortic constriction, CMs contract against increased resistance & hypertrophy mainly occurs by increasing their CSA. In volume overload, as in post-infraction heart failure, myocardial hypertrophy mainly occurs by CM lengthening.

Hamid Agha Alinejad Mechano-receptors in the CMs in both pathologic & physiologic hypertrophy; Signaling via a family of cell surface receptors called integrins Activation of nonreceptor tyrosine kinase by stretch-induced conformational changes Stretch-activated ion channels that induce increased Ca²+

Intracellular calcium Calcineurin/NFAT pathway Necessary mechanism of pathologic hypertrophy, heart failure & premature death (Wilkins & Molkentin, 2002),whereas physiological hypertrophy in response to exercise training dose not seem to involve this pathway (Wilkins et al., 2004). Hamid Agha Alinejad

AKT/mTOR pathway Hamid Agha Alinejad Exercise-induced cardiac growth are regulated by the GH /IGF axis via signaling through the PI3K/Akt or Akt/mTOR pathway. Research evidences: Neri Serneri et al., 2001; Godfrey et al., 2003; McMullen et al., 2003, 2004b; Ceci et al., 2004; Latronico et al., 2004; Dorn and Force, 2005; DeBosch et al., 2006; Walsh, 2006.

Hamid Agha Alinejad Activated Akt proteins phosphorylate a variety of intracellular substrates that regulate growth, metabolism, and survival.

Hamid Agha Alinejad IGF-1 receptor overexpression (McMullen et al., 2004) → activating Akt (Condorelli et al., 2002; Catalucci & Condorelli, 2006) → physiological hypertrophy & enhanced inotropy in the heart & in the CMs (Condorelli et al., 2002; McMullen et al., 2004) by increasing the Ca2‏ currents through the L-type Ca2‏ channel & SERCA (Wang et al., 2005).

Mechanisms of activation of PI3K/Akt signaling in physiological hypertrophy Hamid Agha Alinejad

Hamid Agha Alinejad Physiological growth and hemodynamic adaptability are blunted when Akt-1 is knocked out (DeBosch et al., 2006).

Glycogen synthase kinase–3 (GSK-3) Hamid Agha Alinejad Glycogen synthase kinase–3 (GSK-3) Glycogen synthase kinase–3 (GSK-3) are important negative regulators of protein synthesis that are inhibited by Akt. Akt also phosphorylates and inhibits the product of the TSC2 gene, tuberous sclerosis 2 (TSC2), which itself inhibits the mTOR (Potter et al., 2002; Inoki et al., 2002).

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GSK-3 as a convergence point in hypertrophic signaling Hamid Agha Alinejad

Mitogen Activated Protein Kinase (MAPK) Hamid Agha Alinejad MAPKs are ubiquitous signaling proteins involved in the control of cell growth, function, and adaptation. Mechanical stretch causes activation of MAPK signaling cascades, resulting in the induction of immediate early gene (c-fos, c-jun, and c-myc) expression, and subsequently these induced immediate early genes augment the expression of their target molecules related to hypertrophy of CMs in vitro (Ruwhof & van der Laares, 2000).

Hamid Agha Alinejad Chronic exercise training for 4–12 wk attenuates activation of cardiac MAPK signaling pathways by a single bout of exercise. Thus, acute exercise-induced activation of multiple cardiac MAPK pathways gradually declines with development of exercise training-induced cardiac hypertrophy (Iemitsu et al., 2006).

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