Talin1 Has Unique Expression versus Talin 2 in the Heart and Modifies the Hypertrophic Response to Pressure Overload

Manso, Ana Maria; Li, Ruixia; Monkley, Susan J.; Cruz, Nathalia M.; Ong, Shannon; Lao, Dieu Hung; Koshman, Yevgeniya E.; Gu, Yusu; Peterson, Kirk L.; Chen, Ju; Abel, E. Dale; Samarel, Allen M.; Critchley, David R.; Ross, Robert S.

doi:10.1074/jbc.m112.427484

Cited by 69 publications

(77 citation statements)

References 48 publications

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“…Tln2 is the major Tln isoform in adult CMs (17). To study its role in the heart, we used Tln2 knockout (KO) mice.…”

Section: Resultsmentioning

confidence: 99%

“…S6C). Furthermore, prior work by ourselves and others with this specific Cre mouse line has shown no evidence of heart failure (17,(32)(33)(34).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

“…Although Tln is mainly localized at costameres, it has also been detected at low levels in ICDs (17). Therefore, we analyzed the expression levels of ICD proteins in adherens and gap junctions, as well as in desmosomes.…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

“…For this, we crossed the Tln1 CM-specific KO mice (Tln1flox/flox × α-MHCCre) that we generated previously (17) (Tln1cKO) with Tln2KO mice. In our prior studies, we showed that the α-MCH-Cre transgene is active beginning at E10.5 during heart development (17). Tln1cKO/Tln2KO mice were born at expected Mendelian ratios (SI Appendix, Table S4) and appeared morphologically normal at birth.…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

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Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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“…Tln2 is the major Tln isoform in adult CMs (17). To study its role in the heart, we used Tln2 knockout (KO) mice.…”

Section: Resultsmentioning

confidence: 99%

“…S6C). Furthermore, prior work by ourselves and others with this specific Cre mouse line has shown no evidence of heart failure (17,(32)(33)(34).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 99%

See 2 more Smart Citations

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Both isoforms are highly expressed in cardiomyocytes, but during maturation, and in the mature heart, talin2 becomes the major isoform, localising to the costameres 111. Indeed, cardiac‐specific talin1 knockout mice show normal basal cardiac function.…”

Section: Talin2 In Disease and Developmentmentioning

confidence: 99%

The tale of two talins – two isoforms to fine‐tune integrin signalling

Gough

Goult

2018

FEBS Letters

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Talins are cytoplasmic adapter proteins essential for integrin‐mediated cell adhesion to the extracellular matrix. Talins control the activation state of integrins, link integrins to cytoskeletal actin, recruit numerous signalling molecules that mediate integrin signalling and coordinate recruitment of microtubules to adhesion sites via interaction with KANK (kidney ankyrin repeat‐containing) proteins. Vertebrates have two talin genes, TLN1 and TLN2. Although talin1 and talin2 share 76% protein sequence identity (88% similarity), they are not functionally redundant, and the differences between the two isoforms are not fully understood. In this Review, we focus on the similarities and differences between the two talins in terms of structure, biochemistry and function, which hint at subtle differences in fine‐tuning adhesion signalling.

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Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

208

181

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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Talin1 Has Unique Expression versus Talin 2 in the Heart and Modifies the Hypertrophic Response to Pressure Overload

Cited by 69 publications

References 48 publications

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

The tale of two talins – two isoforms to fine‐tune integrin signalling

Overview of the Muscle Cytoskeleton

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