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Biomolecules Oct 2023Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; Motor Neurons; Muscle, Skeletal; Muscular Atrophy; Paralysis
PubMed: 38002264
DOI: 10.3390/biom13111582 -
Brain : a Journal of Neurology Oct 2023Centronuclear and myotubular myopathies (CNM) are rare and severe genetic diseases associated with muscle weakness and atrophy as well as intracellular disorganization...
Centronuclear and myotubular myopathies (CNM) are rare and severe genetic diseases associated with muscle weakness and atrophy as well as intracellular disorganization of myofibres. The main mutated proteins control lipid and membrane dynamics and are the lipid phosphatase myotubularin (MTM1), and the membrane remodelling proteins amphiphysin 2 (BIN1) and dynamin 2 (DNM2). There is no available therapy. Here, to validate a novel therapeutic strategy for BIN1- and DNM2-CNM, we evaluated adeno-associated virus-mediated MTM1 (AAV-MTM1 ) overexpression in relevant mouse models. Early systemic MTM1 overexpression prevented the development of the CNM pathology in Bin1mck-/- mice, while late intramuscular MTM1 expression partially reverted the established phenotypes after only 4 weeks of treatment. However, AAV-MTM1 injection did not change the DNM2-CNM mouse phenotypes. We investigated the mechanism of the rescue of the myopathy in BIN1-CNM and found that the lipid phosphatase activity of MTM1 was essential for the rescue of muscle atrophy and myofibre hypotrophy but dispensable for the rescue of myofibre disorganization including organelle mis-position and T-tubule defects. Furthermore, the improvement of T-tubule organization correlated with normalization of key regulators of T-tubule morphogenesis, dysferlin and caveolin. Overall, these data support the inclusion of BIN1-CNM patients in an AAV-MTM1 clinical trial.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Dynamin II; Lipids; Muscle, Skeletal; Muscular Atrophy; Mutation; Myopathies, Structural, Congenital; Nuclear Proteins; Phenotype; Tumor Suppressor Proteins; Protein Tyrosine Phosphatases, Non-Receptor; Genetic Therapy
PubMed: 37490306
DOI: 10.1093/brain/awad251 -
Journal of Cellular Physiology Jul 2023Sarcopenia is an elderly disease and is related to frailty and loss of muscle mass (atrophy) of older adults. The exact molecular mechanisms contributing to the... (Review)
Review
Sarcopenia is an elderly disease and is related to frailty and loss of muscle mass (atrophy) of older adults. The exact molecular mechanisms contributing to the pathogenesis of disease are yet to be discovered. In recent years, the role of noncoding RNAs in the pathogenesis of almost every kind of malignant and nonmalignant conditions is pinpointed. Regarding their regulatory function, there have been an increased number of studies on the role of noncoding RNAs in the progress of sarcopenia. In this manuscript, we review the role of microRNAs and long noncoding RNAs in development and progression of disease. We also discuss their potential as therapeutic targets in this condition.
Topics: Aged; Humans; MicroRNAs; RNA, Long Noncoding; RNA, Untranslated; Sarcopenia
PubMed: 37183312
DOI: 10.1002/jcp.31031 -
Current Opinion in Pharmacology Aug 2023The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years... (Review)
Review
The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years later by Dr. W. Kennedy. SBMA is a neuromuscular disease caused by expansions of a CAG microsatellite tandem repeat in exon 1 of the androgen receptor (AR) gene located on the X chromosome. These expansions result in the production of AR with an aberrantly expanded polyglutamine (polyQ) tract. In this review, we explore recent advancements in the significance of gene expression changes in skeletal muscle and discuss how pharmacological interventions targeting this aspect of disease pathogenesis can potentially be translated into therapies for SBMA patients.
Topics: Humans; Bulbo-Spinal Atrophy, X-Linked; Receptors, Androgen; Muscle, Skeletal; Muscular Atrophy
PubMed: 37463556
DOI: 10.1016/j.coph.2023.102394 -
Cell Reports. Medicine Dec 2023Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic...
Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic approaches. We identified two promoters of "BMP resistance" in cancer cachexia, specifically the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling, rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutic potential for targeting the ERFE-FKBP12 axis.
Topics: Humans; Mice; Animals; Cachexia; Tacrolimus; Muscle, Skeletal; Tacrolimus Binding Protein 1A; Muscular Atrophy; Neoplasms
PubMed: 38052214
DOI: 10.1016/j.xcrm.2023.101306 -
Brain and Nerve = Shinkei Kenkyu No... Jan 2024Congenital myasthenic syndromes (CMS) are characterized by congenital defects in the neuromuscular signal transmission and are caused by pathogenic variants in 36 genes....
Congenital myasthenic syndromes (CMS) are characterized by congenital defects in the neuromuscular signal transmission and are caused by pathogenic variants in 36 genes. Recently identified forms of CMS include TOR1AIP1-CMS, CHD8-CMS, PURA-CMS, and TEFM-CMS. Most forms of CMS are caused by autosomal recessive variants, whereas four forms of CMS are caused by autosomal dominant variants, in which adult-onset cases are not rare. As myasthenic features are not always observed and muscle hypotrophy is sometimes observed, CMS should be considered in differential diagnosis of congenital myopathies and other neuromuscular diseases. Low- and high-frequency repetitive nerve stimulation is essential to diagnose CMS for patients who develop muscle weakness at less than 2 years of age. Tubular aggregates are observed in muscle biopsy in four forms of CMS, and serum CK levels are elevated in some forms of CMS. As rational therapies are available for most forms of CMS, identification of causative gene variants by genetic analysis is required.
Topics: Adult; Humans; Myasthenic Syndromes, Congenital; Biopsy; Diagnosis, Differential; Muscle Weakness; Muscular Atrophy
PubMed: 38191138
DOI: 10.11477/mf.1416202556 -
Journal of Cachexia, Sarcopenia and... Feb 2024Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed... (Meta-Analysis)
Meta-Analysis Review
Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed sarcopenia. The extent of skeletal muscle wasting in clinical and preclinical CKD populations is unclear. We evaluated skeletal muscle atrophy in preclinical and clinical models of CKD, with multiple sub-analyses for muscle mass assessment methods, CKD severity, sex and across the different preclinical models of CKD. We performed a systematic literature review of clinical and preclinical studies that measured muscle mass/size using the following databases: Ovid Medline, Embase and Scopus. A random effects meta-analysis was utilized to determine standard mean difference (SMD; Hedges' g) between healthy and CKD. Heterogeneity was evaluated using the I statistic. Preclinical study quality was assessed via the Systematic Review Centre for Laboratory Animal Experimentation and clinical studies quality was assessed via the Newcastle-Ottawa Scale. This study was registered in PROSPERO (CRD42020180737) prior to initiation of the search. A total of 111 studies were included in this analysis using the following subgroups: 106 studies in the primary CKD analysis, 18 studies that accounted for diabetes and 7 kidney transplant studies. Significant atrophy was demonstrated in 78% of the preclinical studies and 49% of the clinical studies. The random effects model demonstrated a medium overall SMD (SMD = 0.58, 95% CI = 0.52-0.64) when combining clinical and preclinical studies, a medium SMD for the clinical population (SMD = 0.48, 95% CI = 0.42-0.55; all stages) and a large SMD for preclinical CKD (SMD = 0.95, 95% CI = 0.76-1.14). Further sub-analyses were performed based upon assessment methods, disease status and animal model. Muscle atrophy was reported in 49% of the clinical studies, paired with small mean differences. Preclinical studies reported significant atrophy in 78% of studies, with large mean differences. Across multiple clinical sub-analyses such as severity of CKD, dialysis modality and diabetes, a medium mean difference was found. Sub-analyses in both clinical and preclinical studies found a large mean difference for males and medium for females suggesting sex-specific implications. Muscle atrophy differences varied based upon assessment method for clinical and preclinical studies. Limitations in study design prevented conclusions to be made about the extent of muscle loss with disease progression, or the impact of dialysis. Future work would benefit from the use of standardized measurement methods and consistent clinical staging to improve our understanding of atrophy changes in CKD progression, and analysis of biological sex differences.
Topics: Humans; Female; Male; Renal Insufficiency, Chronic; Muscular Atrophy; Renal Dialysis; Muscle, Skeletal; Diabetes Mellitus
PubMed: 38062879
DOI: 10.1002/jcsm.13400 -
Frontiers in Endocrinology 2023Age-related muscle atrophy and adipose accumulation begin to occur in young and middle-aged individuals, and exercise at an early age improves body composition....
BACKGROUND
Age-related muscle atrophy and adipose accumulation begin to occur in young and middle-aged individuals, and exercise at an early age improves body composition. Pyroptosis may play an essential role in age-related low-grade inflammation. This study aimed to explore the alleviation of muscle atrophy by weight-bearing training with increasing age inhibition of pyroptosis.
METHODS
Ninety 8-month-old male SD rats were randomly divided into three groups: (1) normal baseline group (N group, = 10), sacrificed after adaptive feeding; control group (C group, = 40); and weight-bearing running group (R group, = 40). Blood samples, adipose tissue (AT), and extensor digitorum longus (EDL) were collected after 8, 16, 24, and 32-weeks intervention.
RESULTS
The body weight, muscle mass, fat mass, plasma lipid, AT wet weight, adipocyte cross-sectional area (CSA), and apoptosis rates of AT and EDL were increased, while the muscle mass, wet weight, and fiber CSA of EDL were decreased by aging, which were reversed by exercise. Weight-bearing training promoted protein synthesis in EDL, inhibited protein degradation in EDL, and expression of pyroptotic key proteins in EDL and AT in rats.
CONCLUSION
Weight-bearing training improves body composition and alleviates age-related muscle atrophy in rats, and its mechanism may be related to the inhibition of pyroptosis in the EDL and AT and the improvement of muscle protein metabolism.
Topics: Male; Animals; Rats; Rats, Sprague-Dawley; Pyroptosis; Muscular Atrophy; Muscles; Adipose Tissue
PubMed: 37720530
DOI: 10.3389/fendo.2023.1202686 -
Current Opinion in Clinical Nutrition... Jul 2023Cancer cachexia results in the death of approximately 2 million people worldwide annually. Despite the impact of this devastating condition, there is limited therapy and... (Review)
Review
PURPOSE OF REVIEW
Cancer cachexia results in the death of approximately 2 million people worldwide annually. Despite the impact of this devastating condition, there is limited therapy and no standard of care. Although multiple definitions exist, confusion remains as a true understanding of the biology has not yet been achieved and distinct phases of cachexia have not been examined. Research has mainly focused on weight loss and muscle wasting, but cachexia is increasingly recognized as a multiorgan disorder involving adipose tissue, liver, brain, gut and heart, with systemic inflammation a central unifying feature.
RECENT FINDINGS
In this review, we will discuss some of the extra-muscular features and multisystem interactions in cachexia, and describe how moving our focus beyond muscle can lead to a greater understanding of the mechanisms and clinical features seen in cachexia.
SUMMARY
We describe the need for robust characterization of patients with cachexia, to allow clinical phenotypes and multisystem mechanisms to be untangled, and to enable the implementation of multimodal treatment strategies.
Topics: Humans; Cachexia; Neoplasms; Adipose Tissue; Muscular Atrophy; Liver; Muscle, Skeletal
PubMed: 37265093
DOI: 10.1097/MCO.0000000000000951 -
RoFo : Fortschritte Auf Dem Gebiete Der... Sep 2023Sarcopenia, a progressive reduction of muscle mass and function, is associated with adverse outcomes in the elderly. Sarcopenia and muscle atrophy are not equal...
BACKGROUND
Sarcopenia, a progressive reduction of muscle mass and function, is associated with adverse outcomes in the elderly. Sarcopenia and muscle atrophy are not equal processes. Low muscle strength in association with muscle quantity/quality reduction is currently the optimal method for assessing sarcopenia. There is a practical need for indirect measurement of muscle strength using state-of-the-art imaging techniques.
METHODS
The following provides a narrative, broad review of all current imaging techniques for evaluating muscles and identifying sarcopenia, including DEXA, CT, MRI, and high-resolution ultrasound, their main strengths, weaknesses, and possible solutions to problems regarding each technique.
RESULTS AND CONCLUSION
Well-recognized imaging methods for the assessment of muscle mass are explained, including evaluation with DEXA, CT, and MRI muscle quantity assessment, ultrasound evaluation of muscle thickness and CSA, and their correlations with established muscle mass calculation methods. A special focus is on imaging methods for muscle quality evaluation. Several innovative and promising techniques that are still in the research phase but show potential in the assessment of different properties of muscle quality, including MRI DIXON sequences, MRI spectroscopy, Diffusion Tensor Imaging, ultrasound echo intensity, ultrasound elastography, and speed-of-sound ultrasound imaging are briefly mentioned.
KEY POINTS
· Sarcopenia definition includes low muscle strength and low muscle quantity/quality.. · DEXA is a low-radiation method for whole-body composition measurement in a single image.. · CT has established cut-off values for muscle quality/quantity evaluation and sarcopenia diagnosis.. · MRI is the most sophisticated muscle quality assessment method capable of evaluating myosteatosis, myofibrosis, and microstructure.. · Ultrasound can evaluate muscle quality, including tissue architecture, and elasticity with excellent spatial resolution..
CITATION FORMAT
· Vasilevska Nikodinovska V, Ivanoski S, . Sarcopenia, More Than Just Muscle Atrophy: Imaging Methods for the Assessment of Muscle Quantity and Quality. Fortschr Röntgenstr 2023; 195: 777 - 789.
Topics: Humans; Aged; Sarcopenia; Muscle, Skeletal; Diffusion Tensor Imaging; Magnetic Resonance Imaging; Body Composition
PubMed: 37160148
DOI: 10.1055/a-2057-0205