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Nutrients Jun 2021Imbalance of protein homeostasis, with excessive protein degradation compared with protein synthesis, leads to the development of muscle atrophy resulting in a decrease... (Review)
Review
Imbalance of protein homeostasis, with excessive protein degradation compared with protein synthesis, leads to the development of muscle atrophy resulting in a decrease in muscle mass and consequent muscle weakness and disability. Potential triggers of muscle atrophy include inflammation, malnutrition, aging, cancer, and an unhealthy lifestyle such as sedentariness and high fat diet. Nutraceuticals with preventive and therapeutic effects against muscle atrophy have recently received increasing attention since they are potentially more suitable for long-term use. The implementation of nutraceutical intervention might aid in the development and design of precision medicine strategies to reduce the burden of muscle atrophy. In this review, we will summarize the current knowledge on the importance of nutraceuticals in the prevention of skeletal muscle mass loss and recovery of muscle function. We also highlight the cellular and molecular mechanisms of these nutraceuticals and their possible pharmacological use, which is of great importance for the prevention and treatment of muscle atrophy.
Topics: Amino Acids; Animals; Databases, Factual; Dietary Supplements; Fatty Acids; Humans; Inflammation; Minerals; Muscle, Skeletal; Muscular Atrophy; Peptides; Phytochemicals; Probiotics; Proteins; Proteolysis; Vitamins
PubMed: 34199575
DOI: 10.3390/nu13061914 -
The British Journal of General Practice... Dec 2021
Topics: Atrophy; Humans; Urogenital System
PubMed: 34824066
DOI: 10.3399/bjgp21X717725 -
International Journal of Molecular... Dec 2020This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of... (Review)
Review
This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of the proinflammatory cytokine families and release of factors stored in bone during resorption. The juxtaposition of the catabolic and anabolic resorption-dependent pathways raises new questions about control of release of factors from bone, quantity of release in a variety of conditions, and relation of factors released from bone. The catabolic responses involve release of calcium from bone into the circulation resulting in increased inflammatory response in intensity and/or duration. The release of transforming growth factor beta (TGF-β) from bone suppresses phosphorylation of the AKT/mTOR pathway and stimulates ubiquitin-mediated breakdown of muscle protein. In contrast, muscle IL-6 production is stimulated by undercarboxylated osteocalcin, which signals osteoblasts to produce more RANK ligand, stimulating resorptive release of undercarboxylated osteocalcin, which in turn stimulates muscle fiber nutrient uptake and an increase in muscle mass.
Topics: Animals; Bone Resorption; Humans; Muscular Atrophy
PubMed: 33396572
DOI: 10.3390/ijms22010392 -
PloS One 2023Pseudoexfoliation (PEX) syndrome is an age-related disorder characterized by the accumulation of extracellular material in the anterior eye segment. PEX pathogenesis is... (Review)
Review
BACKGROUND/AIMS
Pseudoexfoliation (PEX) syndrome is an age-related disorder characterized by the accumulation of extracellular material in the anterior eye segment. PEX pathogenesis is not fully understood, but amyloid which accumulates in the brain of patients with Alzheimer's disease (AD) is a PEX component. PEX deposition shares features with amyloid aggregation in AD, and brain atrophy is a common AD feature, with β-amyloid accumulation among contributing factors. This study investigated whether PEX syndrome is associated with AD-related brain atrophy.
METHODS
We reviewed the medical records of patients diagnosed with PEX at the Veterans Health Service Medical Center between January 2015 and August 2021. This retrospective cohort study included 48 patients with PEX and 48 healthy age- and sex-matched controls. Patients with PEX were divided into two groups: with and without glaucoma. The main outcome measure was brain atrophy, using a visual rating scale, and AD incidence. Brain atrophy was measured using the Scheltens scale for medial temporal atrophy, the posterior cortical atrophy scale for parietal atrophy, and the Pasquier scale for global cortical atrophy.
RESULTS
The percentage of participants with medial temporal atrophy was 56.3% in the PEX group and 35.4% in the control group. The global cortical atrophy and parietal atrophy scores were significantly higher in the PEX group (P<0.05), whereas the PEX and PEX glaucoma groups showed no difference. Among the 96 participants, 16 and 5 participants in the PEX and control groups, respectively, were diagnosed with dementia. Patients with PEX glaucoma tended to have lower Mini-Mental State Examination scores, indicating impaired cognitive function, than those without glaucoma.
CONCLUSION
PEX is associated with brain atrophy, reflecting the risk of developing AD. Patients with PEX glaucoma may present with advanced AD stages. Our results suggest that PEX may be a predictor of AD.
Topics: Humans; Alzheimer Disease; Retrospective Studies; Glaucoma; Exfoliation Syndrome; Brain; Atrophy
PubMed: 37289754
DOI: 10.1371/journal.pone.0286727 -
Translational Neurodegeneration Dec 2023TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal...
BACKGROUND
TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.
METHODS
We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.
RESULTS
SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.
CONCLUSIONS
Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Neurodegenerative Diseases; Brain; DNA-Binding Proteins; Atrophy
PubMed: 38062485
DOI: 10.1186/s40035-023-00389-3 -
Brain : a Journal of Neurology Nov 2023Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a...
Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.
Topics: Humans; Brain; Artificial Intelligence; Cross-Sectional Studies; Magnetic Resonance Imaging; Epilepsy; Atrophy
PubMed: 37807084
DOI: 10.1093/brain/awad284 -
Transplantation Jan 2024This review outlines the molecular disease states in kidney transplant biopsies as documented in the development of the Molecular Microscope Diagnostic System (MMDx).... (Review)
Review
This review outlines the molecular disease states in kidney transplant biopsies as documented in the development of the Molecular Microscope Diagnostic System (MMDx). These states include T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), recent parenchymal injury, and irreversible atrophy-fibrosis. The MMDx project, initiated through a Genome Canada grant, is a collaboration involving many centers. MMDx uses genome-wide microarrays to measure transcript expression, interprets the results using ensembles of machine learning algorithms, and generates a report. Experimental studies in mouse models and cell lines were extensively used to annotate molecular features and interpret the biopsy results. Over time, MMDx revealed unexpected aspects of the disease states: for example, AMR is usually C4d-negative and often DSA-negative, and subtle "Minor" AMR-like states are frequent. Parenchymal injury correlates with both reduced glomerular filtration rate and increased risk of graft loss. In kidneys with rejection, injury features, not rejection activity, are the strongest predictors of graft survival. Both TCMR and AMR produce injury, but TCMR induces immediate nephron injury and accelerates atrophy-fibrosis, whereas AMR induces microcirculation and glomerular damage that slowly leads to nephron failure and atrophy-fibrosis. Plasma donor-derived cell-free DNA levels correlate strongly with AMR activity, acute kidney injury, and in a complex way with TCMR activity. Thus, the MMDx project has documented the molecular processes that underlie the clinical and histologic states in kidney transplants, and provides a diagnostic tool that can be used to calibrate biomarkers, optimize histology interpretation, and guide clinical trials.
Topics: Animals; Mice; Kidney Transplantation; Kidney; Antibodies; Phenotype; Fibrosis; Atrophy; Graft Rejection; Biopsy
PubMed: 37310258
DOI: 10.1097/TP.0000000000004624 -
Cells Dec 2023The maintenance of skeletal muscle mass plays a fundamental role in health and issues associated with quality of life. Mechanical signals are one of the most potent... (Review)
Review
The maintenance of skeletal muscle mass plays a fundamental role in health and issues associated with quality of life. Mechanical signals are one of the most potent regulators of muscle mass, with a decrease in mechanical loading leading to a decrease in muscle mass. This concept has been supported by a plethora of human- and animal-based studies over the past 100 years and has resulted in the commonly used term of 'disuse atrophy'. These same studies have also provided a great deal of insight into the structural adaptations that mediate disuse-induced atrophy. For instance, disuse results in radial atrophy of fascicles, and this is driven, at least in part, by radial atrophy of the muscle fibers. However, the ultrastructural adaptations that mediate these changes remain far from defined. Indeed, even the most basic questions, such as whether the radial atrophy of muscle fibers is driven by the radial atrophy of myofibrils and/or myofibril hypoplasia, have yet to be answered. In this review, we thoroughly summarize what is known about the macroscopic, microscopic, and ultrastructural adaptations that mediated disuse-induced atrophy and highlight some of the major gaps in knowledge that need to be filled.
Topics: Animals; Humans; Quality of Life; Muscle, Skeletal; Muscular Disorders, Atrophic; Muscle Fibers, Skeletal; Atrophy
PubMed: 38132132
DOI: 10.3390/cells12242811 -
EMBO Molecular Medicine Feb 2023Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of...
Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.
Topics: Humans; Iron Chelating Agents; Retinal Diseases; Cell Death; Atrophy
PubMed: 36645044
DOI: 10.15252/emmm.202216525 -
GeroScience Aug 2023Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle...
Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.
Topics: Mice; Animals; Quality of Life; Muscle, Skeletal; Muscular Atrophy; Aging; Mice, Knockout
PubMed: 37014538
DOI: 10.1007/s11357-023-00772-y