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Cells Jan 2024Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of... (Review)
Review
Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of patients with advanced cancer, particularly those who have been diagnosed with pancreatic or gastric cancer, lung cancer, prostate cancer, colon cancer, breast cancer, or leukemias, are impacted by this condition. This syndrome manifests at all stages of cancer and is associated with an unfavorable prognosis. It heightens the susceptibility to surgical complications, chemotherapy toxicity, functional impairments, breathing difficulties, and fatigue. The early detection of patients with cancer cachexia has the potential to enhance both their quality of life and overall survival rates. Regarding this matter, blood biomarkers, although helpful, possess certain limitations and do not exhibit universal application. Additionally, the available treatment options for cachexia are currently limited, and there is a lack of comprehensive understanding of the underlying molecular pathways associated with this condition. Thus, this review aims to provide an overview of molecular mechanisms associated with cachexia and potential therapeutic targets for the development of effective treatments for this devastating condition.
Topics: Male; Humans; Cachexia; Muscular Atrophy; Quality of Life; Muscle, Skeletal; Breast Neoplasms
PubMed: 38334644
DOI: 10.3390/cells13030252 -
Current Topics in Developmental Biology 2024Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as... (Review)
Review
Myocyte fusion is a pivotal process in the development and regeneration of skeletal muscle. Failure during fusion can lead to a range of developmental as well as pathological consequences. This review aims to comprehensively explore the intricate processes underlying myocyte fusion, from the molecular to tissue scale. We shed light on key players, such as the muscle-specific fusogens - Myomaker and Myomixer, in addition to some lesser studied molecules contributing to myocyte fusion. Conserved across vertebrates, Myomaker and Myomixer play a crucial role in driving the merger of plasma membranes of fusing myocytes, ensuring the formation of functional muscle syncytia. Our multiscale approach also delves into broader cell and tissue dynamics that orchestrate the timing and positioning of fusion events. In addition, we explore the relevance of muscle fusogens to human health and disease. Mutations in fusogen genes have been linked to congenital myopathies, providing unique insights into the molecular basis of muscle diseases. We conclude with a discussion on potential therapeutic avenues that may emerge from manipulating the myocyte fusion process to remediate skeletal muscle disorders.
Topics: Humans; Cell Fusion; Animals; Muscle, Skeletal; Muscle Cells; Muscle Proteins
PubMed: 38670716
DOI: 10.1016/bs.ctdb.2024.01.016 -
Aging Cell Mar 2024Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine...
Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age-associated accumulation of immune cells in skeletal muscle. In this study, through cell-cell communication analysis of skeletal muscle single-cell RNA-sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs in vitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation- and etoposide-induced senescence. Compared to non-senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an in vitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages.
Topics: Mice; Animals; Muscle, Skeletal; Macrophages; Cell Differentiation
PubMed: 38115574
DOI: 10.1111/acel.14069 -
Journal of Cellular and Molecular... Nov 2023This study aims to analyse the pathological features of skeletal muscle injury repair by using rats to model responses to different exercise intensities. Eighty-four...
This study aims to analyse the pathological features of skeletal muscle injury repair by using rats to model responses to different exercise intensities. Eighty-four rats were randomly divided into five groups for treadmill exercise. The short-term control, low-intensity, medium-intensity and high-intensity groups underwent gastrocnemius muscle sampling after 6, 8 and 12 weeks of exercise. The long-term high-intensity group underwent optical coherence tomography angiography and sampling after 18 weeks of exercise. RNA sequencing was performed on the muscle samples, followed by the corresponding histological staining. Differentially expressed genes were generally elevated at 6 weeks in the early exercise stage, followed by a decreasing trend. Meanwhile, the study demonstrated a negative correlation between time and the gene modules involved in vascular regulation. The modules associated with muscle remodelling were positively correlated with exercise intensity. Although the expression of many genes associated with common angiogenesis was downregulated at 8, 12 and 18 weeks, we found that muscle tissue microvessels were still increased, which may be closely associated with elevated sFRP2 and YAP1. During muscle injury-remodelling, angiogenesis is characterized by significant exercise time and exercise intensity dependence. We find significant differences in the spatial distribution of angiogenesis during muscle injury-remodelling, which be helpful for the future achievement of spatially targeted treatments for exercise-induced muscle injuries.
Topics: Rats; Animals; Muscle, Skeletal; Muscular Diseases; Physical Conditioning, Animal
PubMed: 37517049
DOI: 10.1111/jcmm.17879 -
Cell Communication and Signaling : CCS Oct 2023The abnormal lipid and glucose metabolisms are linked to the metabolic disorders, tumorigenesis, and fibrotic diseases, which attracts the increasing attention to find... (Review)
Review
The abnormal lipid and glucose metabolisms are linked to the metabolic disorders, tumorigenesis, and fibrotic diseases, which attracts the increasing attention to find out the key molecules involved in the lipid and glucose metabolism as the possible therapeutic targets on these diseases. A transcriptional factor Twist1 has been associated with not only the embryonic development, cancer, and fibrotic diseases, but also the regulation of lipid and glucose metabolism. In this review, we will discuss the roles and mechanisms of Twist1 in the obesity-associated white adipose tissue inflammation and insulin resistance, brown adipose tissue metabolism, fatty acid oxidation, and glucose metabolism in skeletal muscle to provide a rational perspective to consider Twist1 as a potential treatment target in clinic. Video Abstract.
Topics: Humans; Muscle, Skeletal; Lipid Metabolism; Inflammation; Insulin Resistance; Glucose; Lipids
PubMed: 37784111
DOI: 10.1186/s12964-023-01262-6 -
International Journal of Molecular... Feb 2024Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development... (Review)
Review
Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.
Topics: Humans; Aged; Sarcopenia; Mitochondria; Muscle Fibers, Skeletal; TOR Serine-Threonine Kinases; Muscle, Skeletal
PubMed: 38396729
DOI: 10.3390/ijms25042052 -
Nature Communications Nov 2023Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Although recent studies have started to characterize...
Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Although recent studies have started to characterize the heterogeneity of MuSCs, whether a subset of cells with distinct exists within MuSCs remains unanswered. Here, we find that a population of MuSCs, marked by Gli1 expression, is required for muscle regeneration. The Gli1 MuSC population displays advantages in proliferation and differentiation both in vitro and in vivo. Depletion of this population leads to delayed muscle regeneration, while transplanted Gli1 MuSCs support muscle regeneration more effectively than Gli1- MuSCs. Further analysis reveals that even in the uninjured muscle, Gli1 MuSCs have elevated mTOR signaling activity, increased cell size and mitochondrial numbers compared to Gli1 MuSCs, indicating Gli1 MuSCs are displaying the features of primed MuSCs. Moreover, Gli1 MuSCs greatly contribute to the formation of G cells after muscle injury. Collectively, our findings demonstrate that Gli1 MuSCs represents a distinct MuSC population which is more active in the homeostatic muscle and enters the cell cycle shortly after injury. This population functions as the tissue-resident sentinel that rapidly responds to injury and initiates muscle regeneration.
Topics: Humans; Muscle, Skeletal; Zinc Finger Protein GLI1; Satellite Cells, Skeletal Muscle; Muscular Diseases; Cell Differentiation
PubMed: 37914731
DOI: 10.1038/s41467-023-42837-8 -
American Journal of Physiology. Cell... Oct 2023Mitochondria control cellular functions through their metabolic role. Recent research that has gained considerable attention is their ability to transfer between cells....
Mitochondria control cellular functions through their metabolic role. Recent research that has gained considerable attention is their ability to transfer between cells. This has the potential of improving cellular functions in pathological or energy-deficit conditions, but little is known about the role of mitochondrial transfer in sustaining cellular homeostasis. Few studies have investigated the potential of skeletal muscle as a source of healthy mitochondria that can be transferred to other cell types. Thus, we isolated intermyofibrillar mitochondria from murine skeletal muscle and incubated them with host cells. We observed dose- and time-dependent increases in mitochondrial incorporation into myoblasts. This resulted in elongated mitochondrial networks and an enhancement of bioenergetic profile of the host cells. Mitochondrial donation also rejuvenated the functional capacities of the myoblasts when respiration efficiency and lysosomal function were inhibited by complex I inhibitor rotenone and bafilomycin A, respectively. Mitochondrial transfer was accomplished via tunneling nanotubes, extracellular vesicles, gap junctions, and by macropinocytosis internalization. Murine muscle mitochondria were also effectively transferred to human fibroblast cells having mitochondrial DNA mutations, resulting in augmented mitochondrial dynamics and metabolic functions. This improved cell function by diminishing reactive oxygen species (ROS) emission in the diseased cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated in both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost. This mitochondrial trafficking and bioenergetic reprogramming to maintain and revitalize tissue homeostasis could be a useful therapeutic strategy in treating diseases. In our study, we have shown the potential of mouse skeletal muscle intermyofibrillar mitochondria to be transplanted in myoblasts and human fibroblast cells having mitochondrial DNA mutations. This resulted in an augmentation of mitochondrial dynamics and enhancement of bioenergetic profile in the host cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated into both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost.
Topics: Animals; Humans; Mice; Mitochondria; Muscle, Skeletal; Mitochondria, Muscle; DNA, Mitochondrial; Homeostasis
PubMed: 37575060
DOI: 10.1152/ajpcell.00212.2023 -
Cellular and Molecular Life Sciences :... Jan 2024Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and... (Review)
Review
Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.
Topics: Muscle, Skeletal; Stem Cells; Homeostasis; Adipogenesis
PubMed: 38289345
DOI: 10.1007/s00018-023-05096-w -
Muscle quality and not quantity as a predictor of survival in head and neck squamous cell carcinoma.Oral Oncology Oct 2023Sarcopenia is frequent in head and neck squamous cell carcinoma (HNSCC), as a consequence of malnutrition related to risk factors or tumoral mass. Treatment is... (Clinical Trial)
Clinical Trial
BACKGROUND
Sarcopenia is frequent in head and neck squamous cell carcinoma (HNSCC), as a consequence of malnutrition related to risk factors or tumoral mass. Treatment is associated with toxicities that lead to reduced calories intake and muscle mass wasting. Sarcopenia has been negatively associated with tumor control and survival outcomes.
PURPOSE
Our aim is to evaluate the prognostic impact of sarcopenia on overall survival (OS) and progression free survival (PFS) in HNSCC patients undergoing chemoradiation therapy within a prospective clinical trial of chemoradiation vs induction chemotherapy followed by radiation and cetuximab (INTERCEPTOR).
MATERIALS AND METHODS
On baseline CT or MRI, we investigated the association between OS and PFS with radiological markers of sarcopenia, measured at the third cervical vertebra level. We studied paravertebral skeletal muscles area (cm), muscle density (HU), muscle index (cm/m), and intermuscular adipose tissue (IMAT) area (cm).
RESULTS
Imaging of 128 patients was evaluable. We found out that higher body mass index (BMI) was associated with better OS (p = 0.02), and PFS (p = 0.04). Skeletal muscle area (p = 0.02), and IMAT (p = 0.02) were negatively associated with PFS. IMAT was positively correlated with muscle area (Correlation coefficient 0.6, CI95% 0.47-0.7), and negatively associated with muscle density (Correlation coefficient -0.37, CI95% -0.53 - -0.18).
CONCLUSIONS
IMAT can be used as predictor of PFS in HNC patients undergoing chemoradiation therapy. The amount of intermuscular fat deposits induces alterations of muscle quality, without alterations of muscle quantity, influencing patients' prognosis.
Topics: Humans; Head and Neck Neoplasms; Muscle, Skeletal; Prognosis; Prospective Studies; Sarcopenia; Squamous Cell Carcinoma of Head and Neck
PubMed: 37567147
DOI: 10.1016/j.oraloncology.2023.106540