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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Familial RCMs are usually inherited in an autosomal dominant fashion. The coexistence of HCM and RCM phenotypes within the same families, and with identical disease-causing mutations, highlights the importance of modifier genes, epigenetics, and environmental influences in determining the ultimate clinical phenotype. Many of the RCM probands had pathological mutations in either β-myosin heavy chain (MYH7) or the cardiac troponin I gene (TNNI3). Mutations in other sarcomeric genes including troponin T (TTNT2), myosin-binding protein C (MYBPC3), myosin light chains (MYL 2 and 3) and α-cardiac actin (ACTC) have also been described. Hereditary forms of RCM may not typically be a distinct genetic cardiomyopathy; rather, they may represent part of the broad phenotypic spectrum of HCM that is manifested by limited (or absent) hypertrophy and restrictive physiology. Nonsarcomeric mutations have also been identified in RCM and include mutations in myopalladin (MYPN), titin (TTN) and filament-C (FLNC). FLNC is an actin cross-linking protein expressed in the heart and skeletal muscle. Cardiac myocytes show cytoplasmic inclusions suggesting protein aggregates which are specific for filament-C by immunohistochemistry. Desmin-related RCMs are very rare, characterized by intracytoplasmic accumulation of desmin and caused by mutations in the gene for desmin (DES) or alpha-beta crystallin (CRYAB). Disease expression is variable and may involve skeletal muscle alone, cardiac and skeletal muscle simultaneously or cardiac muscle alone. Conduction disease is typically present, and these mutations should be considered in young patients with RCM and atrioventricular block.
Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Andrew C. Fry, Justin X. Nicoll, Luke A. Olsen
Exercise intensity, here defined as the percentage of a person's one-repetition maximum (1RM), directly influences the response and ultimate adaptation of skeletal muscle (Figure 6.2). Indeed, mechanotransducing pathways are thought to be minimally active following low-intensity resistance exercise (less than 50% of the 1RM), whereas high-intensity exercise (greater than 75% of the 1RM) is required for mechanotransduction. In support of this, the beta-1 integrin subunit was shown to be phosphorylated exclusively following maximal resistance exercise, whereas integrin phosphorylation remained unaffected following low-intensity exercise (66). Similarly, the steroidogenic acute regulatory protein (STAR) pathway, a key regulator of cytoskeletal turnover, also increased to a greater degree following acute resistance exercise relative to endurance exercise (93). However, while this was observed in trained subjects, untrained subjects showed no difference in STAR dynamics whether performing endurance or resistance exercise, thus demonstrating one's training status, whether novice or advanced, as a likely contributor. Moreover, a small heat shock protein integral to cytoskeletal integrity, αB-crystallin (CRYAB), was phosphorylated in an intensity-specific manner (81). Specifically, while endurance exercise increased CRYAB to a similar degree as high-intensity exercise, specifically in slow-twitch muscle fibres, CRYAB phosphorylation within fast-twitch fibres was found to be greater following high-intensity exercise. With this in mind, low-intensity exercise carried out to failure has recently shown to recruit both slow- and fast-twitch muscle fibres (121), leading to speculation as to whether maximal loads are required for heightened muscle fibre mechanotransduction. It may be that the degree to which exercise intensity influences mechanotransduction drastically differs between biophysical and biochemical mechanotransduction, with the latter being more responsive to a range of exercise intensity, whereas biophysical mechanotransduction requires a heightened stimulus for activation.
Brainwashed by extracellular vesicles: the role of extracellular vesicles in primary and metastatic brain tumour microenvironment
Published in Journal of Extracellular Vesicles, 2019
A variety of cell types including astrocytes, oligodendrocytes, neurons and microglia are specific to the brain and can play a role in the brain tumour microenvironment. In the brain microenvironment, astrocytes are one of the major host cells that establish interactions with primary and metastatic tumour cells and play major roles in promoting tumour cell survival and growth [58,59]. The current knowledge of the role of astrocyte-derived EVs in primary brain tumours is limited. EV transfer of alpha-crystallin B chain (CRYAB) from astrocytoma U373 cells was demonstrated to be involved in tumour cell resistance to apoptosis, a hallmark of cancer [60]. Whether normal astrocytes in the tumour microenvironment can also promote tumour growth by transferring CRYAB-containing EVs to tumour cells is a potential mechanism that remains to be explored. Moreover, EVs released from astrocytes as well as the U87MG glioblastoma cell line contain mitochondrial DNA [61]. A recent study demonstrated that cancer-associated fibroblasts could transfer their mitochondrial DNA to breast cancer cells via their EVs to induce an escape from metabolic dormancy in the cancer cells [62]. Given these recent findings, it is of interest to determine whether the mitochondrial DNA found in astrocyte EVs can have any effect on the progression of primary and metastatic brain tumours.
Metaproteomics analysis of microbial diversity of human saliva and tongue dorsum in young healthy individuals
Published in Journal of Oral Microbiology, 2019
Alexander Rabe, Manuela Gesell Salazar, Stephan Michalik, Stephan Fuchs, Alexander Welk, Thomas Kocher, Uwe Völker
Pairwise analysis of human proteins revealed that 75 proteins occur in saliva in significantly lower abundance than on the tongue, while 232 proteins were significantly higher in saliva compared to the tongue surface (Figure 7(b)). Many proteins with increased abundance in saliva (Figure 8) play a role in the innate or adaptive immune system (Lypmhocyte cytosolic protein 1 – LCP1 [70]; BPI fold containing family B member 1 – BPIFB1 [71]; Elastase – ELANE [72]; Annexin A3 – ANXA3 [67]). Proteins with a higher abundance on the tongue could be assigned to the cytoskeleton (Figure 8), e.g. Junction plakoglobin (JUP) and Desmoplakin (DSP), playing a role in the regulation of innate immunity (Tripartite motif containing 29 – TRIM29) [73] or prevent possible irreversible protein aggregations as chaperones (Crystallin alpha B – CRYAB).
New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis
Published in Expert Opinion on Investigational Drugs, 2020
Pablo Villoslada, Lawrence Steinman
Significant discoveries have emerged from transcriptome and the proteome analysis of acute and chronic lesions in the MS brain [205,206]. Several amyloid-forming molecules, including Crystallin Alpha B (CRYAB), amyloid precursor protein (APP), major prion protein, and tau, were all found in MS lesions [207]. These amyloid proteins bind to α7 nicotinic AChR and small molecule agonists of α7 NAChR inhibits EAE [208,209]. Small molecule orally available agonists of the α7 NAChR are now under development for the treatment of progressive MS. Complement inhibitors and other protease inhibitors including thrombin inhibitors [207] and serpins were detected in MS lesions [201]. Serpins like α1 antichymotrypsin ameliorated EAE and enhanced expression of Tregs [201,207,213].