Cytoskeletal protein kinases: titin and its relations in mechanosensing

Gautel, Mathias

doi:10.1007/s00424-011-0946-1

Cited by 118 publications

(127 citation statements)

References 145 publications

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“…ab, antibodies; FRK, fractalkine; IP-10, interferon-g-induced protein-10; MIP1a, macrophage inflammatory protein 1a; ns, nonsignificant; VEGF, vascular endothelial growth factor. heavy chain, tropomyosin, troponin (43,44), and titin, which maintains sarcomere integrity (45). At the molecular level, we observed the downregulation of MyoD, MYOG, and contractile/sarcomeric proteins (titin) and the dystrophin complex in myotubes cocultured with the obese VAT adipocytes.…”

Section: Discussionmentioning

confidence: 73%

Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity

et al. 2015

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Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three-dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1b as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders.During obesity, hypertrophy of white adipose tissue (WAT) is associated with fibro-inflammation and cell dysfunction. However, visceral depot (visceral adipose tissue [VAT]) differs from subcutaneous adipose tissue (SAT) by its inflammatory status because of its high infiltration with immune cells such as macrophages, T lymphocytes, and mast cells (1,2). Hence, VAT hypertrophy is considered an important contributor to obesityrelated metabolic and cardiovascular diseases (3). In obese subjects, hypertrophied adipocytes display abnormal secretion of leptin and adiponectin and increased production of numerous inflammatory cytokines and chemokines, leading to a disrupted interorgan communication between VAT and important metabolic peripheral tissues such as liver and skeletal muscle (4). These organs are particularly exposed to free fatty acids and cytokines, mostly interleukin (IL)-6, which are increasingly released by the visceral fat of obese subjects (5,6). Skeletal muscles are one of the major metabolic tissues of the body, playing a pivotal role in glucose and lipid metabolism. There is a growing body of evidence showing the effects of obesity on skeletal muscle dysfunction, such as the development of insulin resistance, as attested to by numerous studies performed

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Section: Discussionmentioning

confidence: 73%

Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity

et al. 2015

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“…67,68 MURFs are E3 ubiquitin ligases whose members have a dual function in myocytes by marking proteins (perhaps also titin) via ubiquitination for proteasomal degradation ( Figure 3) and by regulating a cardiac hypertrophic program triggered by serum response factor. 69,70 The TK domain of titin belongs to the family of Ca 2+ /calmodulindependent myosin light-chain kinases 15,71 and is activated by mechanical force. 72 Activated TK binds the zinc-finger protein neighbor of BRCA1 gene-1, which forms a signaling complex with Sequestosome-1.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

“…69 The latter associates with MURF2 and ubiquitin and links to the autophagy/lysosomal pathway (Figure 3). 15 Additional binding partners of titin at the COOH terminus are FHL2 and calpain-3, suggesting some shared functionality between M-band and I-band titin elements. Important for the stability of the M-band probably is the interaction of titin domain Ig146 with myomesin, which in turn binds myosin.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

286

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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“…Additional evidence for this model is supported by in vitro experiments whereby stretching of the kinase domain leads to activation of the kinase, thus effectively linking mechanosensation to kinase activity ("mechanozymatics") [42]. Moreover titin's kinase domain is linked via nbr1 and p62 to autophagy, a process of regulated protein and or organelle turnover [43].…”

Section: Titin Kinase Mechanosensor Complexmentioning

confidence: 96%