Current Concepts in the Role of Mechanosensing in the Regulation of Cardiac Contractile Function

Review Article

Austin J Clin Med. 2014;1(3): 11015.

Current Concepts in the Role of Mechanosensing in the Regulation of Cardiac Contractile Function

Gerilechaogetu F2, Feng H2, Golden HB2, Nizamutdinov D2, Dostal JD2, Jacob JC2, Afroze SE4,5, Foster DM1, Bowman J2, Ochoa B2, Tong C3,Glaser SS1,4,5 and Dostal DE1,2*

1Central Texas Veterans Health Care System, USA

2Department of Molecular Cardiology, Texas A&M University Health Science Center, USA

3Systems Biology and Translational Medicine, the Texas A&M University Health Science Center, USA

4Scott & White Healthcare - Digestive Disease Research Center, USA

5Department of Internal Medicine, Texas A&M University Health Science Center, USA

*Corresponding author: Dostal DE, Central Texas Veterans Health Care System, Department of Molecular Cardiology, The Texas A&M University System Health Science Center, 1901 South 1st Street, Bldg. 205, Temple TX 76504 USA

Received: May 31, 2014; Accepted: August 05, 2014; Published: August 11, 2014


The heart as a contractile organ finely tunes mechanical parameters such as stroke volume, stroke pressure and cardiac output according to filling volumes, filling pressures via intrinsic and neuronal routes. At the cellular level, cardiac myocytes in beating hearts are exposed to large changes in mechanical stress during successive heart beats. Physical stimuli sensed by cells are transmitted through intracellular signal transduction pathways resulting in altered physiological responses or pathological conditions. Although the mechanisms of excitation-contraction coupling have been well established in mammalian heart cells, the putative contribution of mechanosensitive receptors, channels, signaling factors and force generation has been primarily investigated in relation to heart contraction, growth and leading to heart failure. We present an overview of the current literature and concepts of mechanical sensors residing within the plasma membrane, mechanosensitive receptors induced downstream signaling factors and their potential roles in cardiac contraction and growth.

Keywords: Cardiac myocytes; Mechanosensitive receptors; Signaling; Heart contraction


AT1: Angiotensin II type 1; AT1R: Receptors; APJ: Apelin Receptor; AF: Atrial fibrillation; Ca2++:Calcium ion; CaMKII: Calmodulin Kinase II; cTnC: Cardiac Troponin C; cTnI: Cardiac Troponin I; cTnT: Cardiac troponin T; JNK: c-Jun N- terminal kinases; cAMP: cyclic AMP; DHPR: Dihydropyridine Receptor; DCM: Dilated Cardiomyopathy; ELC: Essential Light-Chain; ECM: Extracellular Matrix; ERK: Extracellular-Regulated Kinase; FAK: Focal Adhesion Kinase; FHL: Four-and-a-half-LIM-domain proteins; GPCR: G Protein-Coupled Receptor; HF: Heart Failure; HRC: Histidine-Rich Ca2++-binding protein; Ig: Immunoglobulin; INCENP: Inner Centromere Protein; IGF-1: Insulin-Like Growth Factor-1; ILK: Integrin-Linked Kinase; IQGAP2: IQ motif containing GTPase-activating protein 2; KIF12: kinesin-6; LINC: Linker of the Nucleoskeleton and Cytoskeleton; MAPKs: Mitogen Activated Protein Kinases; MARPs: Muscle Ankyrin Repeat Proteins; cMyBP-C: Myosin Binding Protein-C; ELC: myosin Essential Light-Chain; MHC: Myosin Heavy-Chain; MLC: Myosin Light-Chain; MLCK: Myosin Light-Chain Kinase; MLCP: Myosin Light-Chain Phosphatase; RLC: myosin Regulatory Light-Chain (); NCX: Na++/Ca2+ exchanger; PI3K: Phosphatidylinositol 3-Kinase; PDK1: Phosphatidylinositol- Dependent Kinase-1; PLB: Phospholamban; PKA: Protein Kinase A; PKB/Akt: Protein Kinase B; PKC: Protein Kinase C; PKG: Protein Kinase G; PP1: Protein Phosphatase-1; PP2A: Protein Phosphatase-2 A; RLC: Regulatory Light-Chain; RyRs: Ryanodine Receptors; SR: Sarcoplasmic Reticulum; SACs: Stretch-Activated Channels; TRPCs : Transient Receptor Potential Channels; α-TM: α-Tropomyosin


About a century ago, Otto Frank in Germany and Ernest Starling in England reported on the relationship between the extent of ventricular filling and pump function of the heart, a phenomenon collectively referred to as Frank-Starling’s Law of the Heart [1]. Frank’s experiments employed the isolated frog heart and suggested that maximum ventricular pressure critically depends on whether the heart is operating under ejecting or isovolumic conditions. Frank-Starling’s Law describes how stretch of cardiac muscle, up to an optimum length, increases contractility thereby linking cardiac ejection to cardiac filling.

The role of mechanical force as an important regulator of structure and function of mammalian cells, tissues, and organs has recently been recognized. Physical stimuli must be sensed by cells and transmitted through intracellular signal transduction pathways to effect or molecules and organelles, resulting in altered physiological responses or pathological conditions. In this research field, significant progress has recently been achieved, especially from studies of cardiovascular systems [2-12].

Cells adhere to the extracellular matrix (ECM) and to each other through specific classes of Tran’s membrane adhesion receptors [13- 15]. These receptors bind to extracellular ligands and provide an anchor to the intracellular cytoskeleton via cytoplasmic scaffolding proteins [16,17]. Linkages between external cellular contacts, adhesion receptors, and cytoskeleton provide a means for bidirectional communication between the inside and outside of a cell. Dynamic changes in adhesions, matrix mechanics and cytoskeletal systems may thus play a critical role in regulating mechanotransduction [18].

The cellular response to mechanical forces is inherently coupled to the internal organization of the cytoskeleton and adhesion to surrounding cells and the ECM [19]. Structural cues such as anisotropy or topography of the ECM or location of cell-to-cell contact can cause a cell to reorient its body, change its shape, or alter its functional state [20-22]. Similarly, changes in the shape and internal organization of cells alter how cells adhere to their surroundings and affect their function [23-25]. Application or removal of a gross external load from a cell causes the cell to actively adapt its adhesions and cytoskeleton and transduce the altered mechanical environment into biochemical signals [26]. Mechanochemical signal transduction originates at the cell membrane, and several candidate sensor molecules have been postulated, including ion channels, tyrosine kinase receptors, G-proteins, enzymes, integrins, and proteins from the cytoskeleton [27]. Besides the common mechanosensing mechanisms shared by various cell types cardiac muscle has intricate intrinsic mechanisms that regulate adaptive remodeling. Z disks and titin filaments generate a complicated mechanical sensor system to receive and transduce stretch signals [28]. Some cardiac specific molecules such as muscle-enriched LIM domain proteins, specialized protein structural domains composed of two contiguous zinc finger domains, separated by a two-amino acid residue hydrophobic linker. PDZ-LIM domain proteins, myozenin gene family members, titin-associated ankyrin repeat family proteins, and muscle-specific ring finger proteins are attributable to this sensing mechanism [28]. The compartmentalization of signaling complexes permits alteration of receptor-dependent transcriptional regulation by direct sensing of mechanical stress. Other muscle-specific membrane systems such costumers [29], intercalated disks [30], and caveolae-like micro domains [31,32] are also recently identified mechanical stress sensors. In the past decade it has become apparent that mechanosensing within the cardiac myocyte is a multifaceted, dynamic and complex process (see Figure 1) that involves a coordinated interaction among plasma membrane mechanoreceptors, stretch-activated channels, downstream signaling factors, cytoskeletal elements, nucleoskeletal proteins that serve to regulate cellular functions such as gene expression, sarcomeric contraction, growth and metabolism.

Citation: Gerilechaogetu F, Feng H, Golden HB, Nizamutdinov D, Dostal JD, et al. Current Concepts in the Role of Mechanosensing in the Regulation of Cardiac Contractile Function. Austin J Clin Med. 2014;1(3): 1015. ISSN : 2381-9146