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Frontiers in Medicine 2023Low muscle mass disproportionately affects people with coronary heart disease compared to healthy controls but is under-researched and insufficiently treated....
BACKGROUND
Low muscle mass disproportionately affects people with coronary heart disease compared to healthy controls but is under-researched and insufficiently treated. Inflammation, poor nutrition, and neural decline might contribute to low muscle mass. This study aimed to assess circulatory biomarkers related to these mechanisms [albumin, transthyretin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-terminal agrin fragment] and their relationship with muscle mass in people with coronary heart disease. Our findings could be beneficial to indicate mechanisms of sarcopenia, detect sarcopenia, and evaluate treatment.
METHODS
Serum blood samples from people with coronary heart disease were analysed for biomarker concentrations using enzyme-linked immunosorbent assays. Skeletal muscle mass was estimated using dual X-ray absorptiometry derived appendicular lean mass and reported as skeletal muscle index (SMI; kg m), and as a proportion of total body mass [appendicular skeletal mass (ASM%)]. Low muscle mass was defined as a SMI <7.0 and <6.0 kg m, or ASM% <25.72 and <19.43% for men and women, respectively. Associations between biomarkers and lean mass were adjusted for age and inflammation.
RESULTS
Sixty-four people were assessed; 14 (21.9%) had low muscle mass. People with low muscle mass had lower transthyretin (effect size 0.34, = 0.007), ALT (effect size 0.34, = 0.008), and AST (effect size 0.26, = 0.037) concentrations, compared to those with normal muscle mass. SMI was associated with inflammation-corrected ALT ( = 0.261, = 0.039) and with inflammation- and age-adjusted AST/ALT ratio ( = -0.257, = 0.044). Albumin and C-terminal agrin fragment were not associated with muscle mass indices.
CONCLUSION
Circulatory transthyretin, ALT and AST were associated with low muscle mass in people with coronary heart disease. Low concentrations of these biomarkers might indicate that low muscle mass is partially explained by poor nutrition and high inflammation in this cohort. Targeted treatments to address these factors could be considered for people with coronary heart disease.
PubMed: 36891188
DOI: 10.3389/fmed.2023.1094733 -
Cellular and Molecular Life Sciences :... Mar 2023Neurotrypsin (NT) is a neuronal trypsin-like serine protease whose mutations cause severe mental retardation in humans. NT is activated in vitro by Hebbian-like...
Neurotrypsin (NT) is a neuronal trypsin-like serine protease whose mutations cause severe mental retardation in humans. NT is activated in vitro by Hebbian-like conjunction of pre- and postsynaptic activities, which promotes the formation of dendritic filopodia via proteolytic cleavage of the proteoglycan agrin. Here, we investigated the functional importance of this mechanism for synaptic plasticity, learning, and extinction of memory. We report that juvenile neurotrypsin-deficient (NT) mice exhibit impaired long-term potentiation induced by a spaced stimulation protocol designed to probe the generation of new filopodia and their conversion into functional synapses. Behaviorally, juvenile NT mice show impaired contextual fear memory and have a sociability deficit. The latter persists in aged NT mice, which, unlike juvenile mice, show normal recall but impaired extinction of contextual fear memories. Structurally, juvenile mutants exhibit reduced spine density in the CA1 region, fewer thin spines, and no modulation in the density of dendritic spines following fear conditioning and extinction in contrast to wild-type littermates. The head width of thin spines is reduced in both juvenile and aged NT mice. In vivo delivery of adeno-associated virus expressing an NT-generated fragment of agrin, agrin-22, but not a shorter agrin-15, elevates the spine density in NT mice. Moreover, agrin-22 co-aggregates with pre- and postsynaptic markers and increases the density and size of presynaptic boutons and presynaptic puncta, corroborating the view that agrin-22 supports the synaptic growth.
Topics: Humans; Animals; Mice; Aged; Peptide Hydrolases; Long-Term Potentiation; Agrin; Dendritic Spines; Memory Disorders
PubMed: 36871239
DOI: 10.1007/s00018-023-04720-z -
Cells Feb 2023Wharton's jelly stem cells (WJSC) from the human umbilical cord (UC) are one of the most promising mesenchymal stem cells (MSC) in tissue engineering (TE) and advanced...
Wharton's jelly stem cells (WJSC) from the human umbilical cord (UC) are one of the most promising mesenchymal stem cells (MSC) in tissue engineering (TE) and advanced therapies. The cell niche is a key element for both, MSC and fully differentiated tissues, to preserve their unique features. The basement membrane (BM) is an essential structure during embryonic development and in adult tissues. Epithelial BMs are well-known, but similar structures are present in other histological structures, such as in peripheral nerve fibers, myocytes or chondrocytes. Previous studies suggest the expression of some BM molecules within the Wharton's Jelly (WJ) of UC, but the distribution pattern and full expression profile of these molecules have not been yet elucidated. In this sense, the aim of this histological study was to evaluate the expression of main BM molecules within the WJ, cultured WJSC and during WJSC microtissue (WJSC-MT) formation process. Results confirmed the presence of a pericellular matrix composed by the main BM molecules-collagens (IV, VII), HSPG2, agrin, laminin and nidogen-around the WJSC within UC. Additionally, ex vivo studies demonstrated the synthesis of these BM molecules, except agrin, especially during WJSC-MT formation process. The WJSC capability to synthesize main BM molecules could offer new alternatives for the generation of biomimetic-engineered substitutes where these molecules are particularly needed.
Topics: Adult; Female; Pregnancy; Humans; Wharton Jelly; Agrin; Umbilical Cord; Mesenchymal Stem Cells; Cell Culture Techniques; Basement Membrane
PubMed: 36831296
DOI: 10.3390/cells12040629 -
Biomedicines Feb 2023Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic...
Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.
PubMed: 36830985
DOI: 10.3390/biomedicines11020449 -
Scientific Reports Feb 2023Blood flow is translated into biochemical inflammatory or anti-inflammatory signals based onshear stress type, by means of sensitive endothelial receptors. Recognition...
Blood flow is translated into biochemical inflammatory or anti-inflammatory signals based onshear stress type, by means of sensitive endothelial receptors. Recognition of the phenomenon is of paramount importance for enhanced insights into the pathophysiological processes of vascular remodeling. The endothelial glycocalyx is a pericellular matrix, identified in both arteries and veins, acting collectively as a sensor responsive to blood flow changes. Venous and lymphatic physiology is interconnected; however, to our knowledge, a lymphatic glycocalyx structure has never been identified in humans. The objective of this investigation is to identify glycocalyx structures from ex vivo lymphatic human samples. Lower limb vein and lymphatic vessels were harvested. The samples were analyzed by transmission electron microscopy. The specimens were also examined by immunohistochemistry. Transmission electron microscopy identified a glycocalyx structure in human venous and lymphatic samples. Immunohistochemistry for podoplanin, glypican-1, mucin-2, agrin and brevican characterized lymphatic and venous glycocalyx-like structures. To our knowledge, the present work reports the first identification of a glycocalyx-like structure in human lymphatic tissue. The vasculoprotective action of the glycocalyx could become an investigational target in the lymphatic system as well, with clinical implications for the many patients affected by lymphatic disorders.
Topics: Humans; Glycocalyx; Immunohistochemistry; Lymphatic Vessels; Microscopy, Electron; Lymphatic System
PubMed: 36810649
DOI: 10.1038/s41598-023-30043-x -
Zoological Research Mar 2023Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular...
Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease, in which lower motoneurons lose control of skeletal muscles. Degeneration of neuromuscular junctions (NMJs) occurs at the initial stage of ALS. Dipeptide repeat proteins (DPRs) from G4C2 repeat-associated non-ATG (RAN) translation are known to cause C9orf72-associated ALS (C9-ALS). However, DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients, indicating that DPRs may exert cell non-autonomous effects, in addition to the known intracellular pathological mechanisms. Here, we report that poly-GA, the most abundant form of DPR in C9-ALS, is released from cells. Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission . The NMJ structure cannot be maintained, as evidenced by the fragmentation of postsynaptic acetylcholine receptor (AChR) clusters and distortion of presynaptic nerve terminals. Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling. Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS. Thus, targeting NMJs could be an early therapeutic intervention for C9-ALS.
Topics: Animals; Agrin; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Dipeptides; Disease Models, Animal
PubMed: 36799225
DOI: 10.24272/j.issn.2095-8137.2022.356 -
Acta Myologica : Myopathies and... 2022Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by...
Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly. This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration.
Topics: Animals; Humans; Receptors, Cholinergic; Myasthenia Gravis; Electromyography; Muscular Atrophy; Muscles; Receptor Protein-Tyrosine Kinases
PubMed: 36793652
DOI: 10.36185/2532-1900-082 -
Eye and Brain 2023Ocular myasthenia gravis (OMG) is a neuromuscular disease characterized by autoantibody production against post-synaptic proteins in the neuromuscular junction. The... (Review)
Review
Ocular myasthenia gravis (OMG) is a neuromuscular disease characterized by autoantibody production against post-synaptic proteins in the neuromuscular junction. The pathophysiological auto-immune mechanisms of myasthenia are diverse, and this is governed primarily by the type of autoantibody production. The diagnosis of OMG relies mainly on clinical assessment, the use of serological antibody assays for acetylcholine receptors (AchR), muscle-specific tyrosine kinase (MusK), and low-density lipoprotein 4 (LPR4). Other autoantibodies against post-synaptic proteins, such as cortactin and agrin, have been detected; however, their diagnostic value and pathogenic effect are not yet clearly defined. Clinical tests such as the ice test and electrophysiologic tests, particularly single-fiber electromyography, have a valuable role in diagnosis. The treatment of OMG is primarily through cholinesterase inhibitors (pyridostigmine), and steroids are frequently required in cases of ophthalmoplegia. Other immunosuppressive therapies include antimetabolites (azathioprine, mycophenolate mofetil, methotrexate) and biological agents such as B-cell depleting agents (Rituximab) and complement inhibitors (eculizumab). Evidence is scarce on the effect of immunosuppressive therapy on altering the natural course of OMG. Clinicians must be vigilant of a myasthenic syndrome in patients using immune-check inhibitors. Reliable and consistent biomarkers are required to assess disease severity and response to therapy to optimize the management of OMG. The purpose of this review is to summarize the current trends and the latest developments in diagnosing and treating OMG.
PubMed: 36778719
DOI: 10.2147/EB.S389629 -
Journal of Cachexia, Sarcopenia and... Apr 2023Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and... (Review)
Review
Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and cardiovascular and pulmonary diseases. This progressive loss of muscle mass and function may also result in the insurgence of a clinical syndrome termed sarcopenia, exacerbated by inactivity and disease. Sarcopenia and muscle weakness yield the risk of falls and injuries, heavily impacting on health and social costs. Thus, screening, monitoring and prevention of conditions inducing muscle wasting and weakness are essential to improve life quality in the ageing modern society. To this aim, the reliability of easily accessible and non-invasive blood-derived biomarkers is being evaluated. C-terminal agrin fragment (CAF) has been widely investigated as a neuromuscular junction (NMJ)-related biomarker of muscle dysfunction. This narrative review summarizes and critically discusses, for the first time, the studies measuring CAF concentration in young and older, healthy and diseased individuals, cross-sectionally and in response to inactivity and physical exercise, providing possible explanations behind the discrepancies observed in the literature. To identify the studies investigating CAF in the above-mentioned conditions, all the publications found in PubMed, written in English and measuring this biomarker in blood from 2013 (when CAF was firstly measured in human serum) to 2022 were included in this review. CAF increases with age and in sarcopenic individuals when compared with age-matched, non-sarcopenic peers. In addition, CAF was found to be higher than controls in other muscle wasting conditions, such as diabetes, COPD, chronic heart failure and stroke, and in pancreatic and colorectal cancer cachectic patients. As agrin is also expressed in kidney glomeruli, chronic kidney disease and transplantation were shown to have a profound impact on CAF independently from muscle wasting. CAF concentration raises following inactivity and seems to be lowered or maintained by exercise training. Finally, CAF was reported to be cross-sectionally correlated to appendicular lean mass, handgrip and gait speed; whether longitudinal changes in CAF are associated with those in muscle mass or performance following physical exercise is still controversial. CAF seems a reliable marker to assess muscle wasting in ageing and disease, also correlating with measurements of appendicular lean mass and muscle function. Future research should aim at enlarging sample size and accurately reporting the medical history of each patient, to normalize for any condition, including chronic kidney disease, that may influence the circulating concentration of this biomarker.
Topics: Humans; Sarcopenia; Agrin; Hand Strength; Reproducibility of Results; Muscular Atrophy; Biomarkers; Renal Insufficiency, Chronic; Muscles
PubMed: 36772862
DOI: 10.1002/jcsm.13189 -
Journal of Cachexia, Sarcopenia and... Apr 2023Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration contribute to sarcopenia pathogenesis. Seeking for strategies able to slow down sarcopenia insurgence and progression, we investigated whether a 2-year mixed-model training involving aerobic, strength and balance exercises would be effective for improving or preserving motoneuronal health and NMJ stability, together with muscle mass, strength and functionality in an old, sarcopenic population.
METHODS
Forty-five sarcopenic elderly (34 females; 11 males) with low dual-energy X-ray absorptiometry (DXA) lean mass and Short Physical Performance Battery (SPPB) score <9 were randomly assigned to either a control group [Healthy Aging Lifestyle Education (HALE), n = 21] or an intervention group [MultiComponent Intervention (MCI), n = 24]. MCI trained three times per week for 2 years with a mix of aerobic, strength and balance exercises matched with nutritional advice. Before and after the intervention, ultrasound scans of the vastus lateralis (VL), SPPB and a blood sample were obtained. VL architecture [pennation angle (PA) and fascicle length (Lf)] and cross-sectional area (CSA) were measured. As biomarkers of neuronal health and NMJ stability status, neurofilament light chain (NfL) and C-terminal agrin fragment (CAF) concentrations were measured in serum. Differences in ultrasound parameters, NfL and CAF concentration and physical performance between baseline and follow-up were tested with mixed ANOVA or Wilcoxon test. The relationship between changes in physical performance and NfL or CAF concentration was assessed through correlation analyses.
RESULTS
At follow-up, MCI showed preserved VL architecture (PA, Lf) despite a reduced CSA (-8.4%, P < 0.001), accompanied by maintained CAF concentration and ameliorated overall SPPB performance (P = 0.007). Conversely, HALE showed 12.7% decrease in muscle CSA (P < 0.001), together with 5.1% and 5.5% reduction in PA and Lf (P < 0.001 and P = 0.001, respectively), and a 6.2% increase in CAF (P = 0.009) but improved SPPB balance score (P = 0.007). NfL concentration did not change in either group. In the population, negative correlations between changes in CAF concentration and SPPB total score were found (P = 0.047), whereas no correlation between NfL and SPPB variations was observed.
CONCLUSIONS
The present findings suggest that our 2-year mixed aerobic, strength and balance training seemed effective for preventing the age and sarcopenia-related increases in CAF concentration, preserving NMJ stability as well as muscle structure (PA and Lf) and improving physical performance in sarcopenic older individuals.
Topics: Male; Female; Humans; Aged; Sarcopenia; Aging; Exercise; Muscle, Skeletal; Absorptiometry, Photon
PubMed: 36708273
DOI: 10.1002/jcsm.13173