When signalling goes wrong: pathogenic variants in structural and signalling proteins causing cardiomyopathies

Ehsan, Mehroz; Thomson, Kate; Gehmlich, Katja

doi:10.1007/s10974-017-9487-3

Cited by 14 publications

(10 citation statements)

References 203 publications

(241 reference statements)

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“…FHL1 localizes to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation, as well as in sarcomere assembly. Recent studies have indicated that mutations in four and-a-half LIM domain protein 1 (FHL1) are associated with rare hereditary myopathies, including reducing body myopathy (RBM), X-Linked myopathy with postural muscle atrophy (XMPMA), Emery-Dreifuss muscular dystrophy (EDMD), and cardiomyopathies ( Kley et al, 2016 ; Xue et al, 2016 ; Ehsan et al, 2017 ; Pillar et al, 2017 ; Le Thanh et al, 2017 ). All these hereditary myopathies exhibit clinical features of muscular dysfunction including progressive muscular weakness, postural muscle atrophy and muscle wasting and weakness ( Schessl et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Protein Turn-Over Associated With Myofibrillar Disorganization in FHL1 Knockout Mice

et al. 2018

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Mutations in the FHL1 gene, and FHL1 protein deletion, are associated with rare hereditary myopathies and cardiomyopathies. FHL1-null mice develop age-dependent myopathy and increased autophagic activity. However, the molecular pathway involved in contractile function and increased autophagic activity in the FHL1-null mouse has not yet been fully elucidated. In this study, FHL1 protein was knocked out in mice using Transcription Activator-like Effector Nucleases (TALENs) and the IRS1-FOXO1/mTOR signaling pathway was investigated in skeletal muscles and heart. TALEN constructs caused targeted mutations in 30% of newborn mice; these mutations caused a deletion of 1–13 base pairs which blocked synthesis of the full-length FHL1 protein. Furthermore, 2.5-month old FHL1-null male mice were not prone to global muscular fatigue when compared with WT littermates, but histological analysis and ultrastructural analysis by transmission electron microscopy confirmed the presence of myofibrillar disorganization and the accumulation of autophagosome or autolysosome-like structures in FHL1-null mice. Moreover, autophagy and mitophagy were both activated in FHL1 KO mice and the degradation of autophagic lysosomes was impeded. Enhanced autophagic activity in FHL1 KO mice was induced by FOXO1 up-regulation and protein synthesis was increased via mTOR. The cytoskeletal proteins, MYBPC2 and LDB3, were involved in the formation of pathological changes in FHL1 KO mice. Markers of early differentiation (MEF2C and MYOD1) and terminal differentiation (total MYH) were both up-regulated in tibialis anterior (TA) muscles in FHL1 KO mice. The number of type I and type II fibers increased in FHL1-null TA muscles, but the number of type| | b, and type | | d fibers were both reduced in FHL1-null TA muscles. The results obtained from the heart were consistent with those from the skeletal muscle and indicated autophagic activation by FOXO1 and an increase in protein synthesis via mTOR also occurred in the heart tissue of FHL1 knockout mice. In conclusion, aberrant protein turn-over associated with myofibrillar disorganization in FHL1 knockout mice. the up-regulation of FOXO1 was associated with enhanced autophagic activity and pathological changes in the muscle fibers of FHL1 KO mice. These results indicated that autophagy activated by FOXO1 is a promising therapeutic target for hereditary myopathies and cardiomyopathies induced by FHL1.

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Section: Discussionmentioning

confidence: 99%

Aberrant Protein Turn-Over Associated With Myofibrillar Disorganization in FHL1 Knockout Mice

et al. 2018

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“…CSRP3 (Muscle LIM Protein) MLP KO cardiomyocytes exhibit cytoarchitectural perturbations including disrupted myofibrillar assembly, abnormal alignment of Z-disks and marked fibrosis. In contrast, for some (but not all) HCM/RCM patients with Filamin C pathogenic variants, protein aggregation has been observed in vivo and in vitro 3 .…”

Section: Pathological Differential Diagnosis Of Hcmmentioning

confidence: 93%

“…Hypertrophic cardiomyopathy is most frequently a disease of the sarcomeric proteins. Mutations in several genes encoding thin and thick filament and the Z disk proteins of the sarcomeres ( MYH7, TPM1, TNNT2, MYBPC3, FHL1, CSRP3, FLNC, PLN) have been described 3 . The histopathological appearance varies according to the genetic defect, with the most severe morphological abnormalities being present in pediatric and early onset cases 4 .…”

Section: Pathological Differential Diagnosis Of Hcmmentioning

confidence: 99%

Histopathology in HCM

Tejado

Jou

2018

gcsp

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[first paragraph of article]Histopathology in patients with HCM is characterized by disarray of the overall architecture of the hypertrophied myocytes, which appear branched and may be intermingled with a variable amount of interstitial fibrosis. These changes may be patched and must be distinguished from the non-specific physiological disarrangement of the junctional area of the septum and the apex. The myocardial cell diameter is another important indicator of hypertrophy. Under normal conditions it ranges from 5–12 μm in diameter. Anything up to 20 μm may be indicative of mild hypertrophy. In moderate hypertrophy cardiocyte diameter is up to 25 μm and moderate to severe hypertrophy is usually between 25-30 μm. For diameters greater than 30 μm severe hypertrophy must be suspected.

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“…Titin is supposed to "…sense the mechanical stimuli and transform them into biochemical signals…" [34]. Great attention is now focused on the study of titin role in cardiomyopathies and skeletal muscle diseases [2,[39][40][41][42][43][44][45][46][47].…”

Section: Electrophoresis -Life Sciences Practical Applications 46mentioning

confidence: 99%

Peculiarities of SDS-PAGE of Titin/Connectin

Vikhlyantsev¹,

Podlubnaya²

2018

Electrophoresis - Life Sciences Practical Applications

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Titin (also known as connectin) is a giant elastic protein of striated and smooth muscles of vertebrates. The molecular weight of its isoforms is 3.0-3.7 MDa in striated muscles and 0.5-2.0 MDa in smooth muscles. Titin was discovered 40 years ago using the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). At the present time, this method has not lost its relevance but has undergone a number of modifications that improve visualization of giant titin isoforms in the gel. This chapter provides historical insights into the technical aspects of the electrophoresis methods used to identify titin and its isoforms. We focus on the peculiarities of the technique because of which titin molecules remain intact and its high molecular weight isoforms can be visualized. Electrophoretic testing of changes in titin content in muscles can be used in medical practice to diagnose pathological processes and evaluate effective approaches to their correction. Figure 7. Increased proteolysis of titin and reduction of T1 content in m. Soleus of post-apoplectic patient. Vertical agarose-strengthened 2.3% polyacrylamide gel (8.0 × 10.0 × 0.10 cm) was used to separate titin isoforms. (1) Human m. soleus (control); (2) m. soleus of post-apoplectic patient.

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When signalling goes wrong: pathogenic variants in structural and signalling proteins causing cardiomyopathies

Cited by 14 publications

References 203 publications

Aberrant Protein Turn-Over Associated With Myofibrillar Disorganization in FHL1 Knockout Mice

Aberrant Protein Turn-Over Associated With Myofibrillar Disorganization in FHL1 Knockout Mice

Histopathology in HCM

Peculiarities of SDS-PAGE of Titin/Connectin

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