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Nature Communications Jun 2023Large temperature difference is reported to be a risk factor for human health. However, little evidence has reported the effects of temperature fluctuation on...
Large temperature difference is reported to be a risk factor for human health. However, little evidence has reported the effects of temperature fluctuation on sarcopenia, a senile disease characterized by loss of muscle mass and function. Here, we demonstrate that higher diurnal temperature range in humans has a positive correlation with the prevalence of sarcopenia. Fluctuated temperature exposure (10-25 °C) accelerates muscle atrophy and dampens exercise performance in mid-aged male mice. Interestingly, fluctuated temperature alters the microbiota composition with increased levels of Parabacteroides_distasonis, Duncaniella_dubosii and decreased levels of Candidatus_Amulumruptor, Roseburia, Eubacterium. Transplantation of fluctuated temperature-shaped microbiota replays the adverse effects on muscle function. Mechanically, we find that altered microbiota increases circulating aminoadipic acid, a lysine degradation product. Aminoadipic acid damages mitochondrial function through inhibiting mitophagy in vitro. And Eubacterium supplementation alleviates muscle atrophy and dysfunction induced by fluctuated temperature. Our results uncover the detrimental impact of fluctuated temperature on muscle function and provide a new clue for gut-muscle axis.
Topics: Humans; Male; Animals; Mice; Middle Aged; Gastrointestinal Microbiome; Sarcopenia; Temperature; Muscular Atrophy; Microbiota; Eubacterium
PubMed: 37311782
DOI: 10.1038/s41467-023-39171-4 -
International Journal of Molecular... Oct 2020Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after... (Review)
Review
Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models.
Topics: Animals; COVID-19; Coronavirus Infections; Critical Care; Humans; Iatrogenic Disease; Muscle Weakness; Muscular Atrophy; Pandemics; Pneumonia, Viral
PubMed: 33105809
DOI: 10.3390/ijms21217840 -
International Journal of Molecular... Sep 2020Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in... (Review)
Review
Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in elderly patients with chronic diseases. The prevalence of sarcopenia in chronic heart failure (HF) patients amounts to up to 20% and may progress into cardiac cachexia. Muscle wasting is a strong predictor of frailty and reduced survival in HF patients. Despite many different techniques and clinical tests, there is still no broadly available gold standard for the diagnosis of sarcopenia. Resistance exercise and nutritional supplementation represent the currently most used strategies against wasting disorders. Ongoing research is investigating skeletal muscle mitochondrial dysfunction as a new possible target for pharmacological compounds. Novel agents such as synthetic ghrelin and selective androgen receptor modulators (SARMs) seem promising in counteracting muscle abnormalities but their effectiveness in HF patients has not been assessed yet. In the last decades, many advances have been accomplished but sarcopenia remains an underdiagnosed pathology and more efforts are needed to find an efficacious therapeutic plan. The purpose of this review is to illustrate the current knowledge in terms of pathogenesis, diagnosis, and treatment of sarcopenia in order to provide a better understanding of wasting disorders occurring in chronic heart failure.
Topics: Aged; Aged, 80 and over; Cachexia; Chronic Disease; Exercise; Heart Failure; Humans; Middle Aged; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Sarcopenia
PubMed: 32911600
DOI: 10.3390/ijms21186549 -
Developmental Cell Nov 2023Thymus is necessary for lifelong immunological tolerance and immunity. It displays a distinctive epithelial complexity and undergoes age-dependent atrophy. Nonetheless,...
Thymus is necessary for lifelong immunological tolerance and immunity. It displays a distinctive epithelial complexity and undergoes age-dependent atrophy. Nonetheless, it also retains regenerative capacity, which, if harnessed appropriately, might permit rejuvenation of adaptive immunity. By characterizing cortical and medullary compartments in the human thymus at single-cell resolution, in this study we have defined specific epithelial populations, including those that share properties with bona fide stem cells (SCs) of lifelong regenerating epidermis. Thymic epithelial SCs display a distinctive transcriptional profile and phenotypic traits, including pleiotropic multilineage potency, to give rise to several cell types that were not previously considered to have shared origin. Using here identified SC markers, we have defined their cortical and medullary niches and shown that, in vitro, the cells display long-term clonal expansion and self-organizing capacity. These data substantively broaden our knowledge of SC biology and set a stage for tackling thymic atrophy and related disorders.
Topics: Humans; Cell Differentiation; Stem Cells; Thymus Gland; Cells, Cultured; Epithelial Cells; Atrophy
PubMed: 37652013
DOI: 10.1016/j.devcel.2023.08.017 -
The Journal of Nutrition, Health & Aging 2021The condition of muscle fiber atrophy and weakness that occurs in respiratory muscles along with systemic skeletal muscle with age is known as respiratory sarcopenia....
The condition of muscle fiber atrophy and weakness that occurs in respiratory muscles along with systemic skeletal muscle with age is known as respiratory sarcopenia. The Japanese Working Group of Respiratory Sarcopenia of the Japanese Association of Rehabilitation Nutrition narratively reviews these areas, and proposes the concept and diagnostic criteria. We have defined respiratory sarcopenia as "whole-body sarcopenia and low respiratory muscle mass followed by low respiratory muscle strength and/or low respiratory function." Respiratory sarcopenia can be caused by various factors such as aging, decreased activity, undernutrition, disease, cachexia, and iatrogenic causes. We have also created an algorithm for diagnosing respiratory sarcopenia. Respiratory function decreases with age in healthy older people, along with low respiratory muscle mass and strength. We have created a new term, "Presbypnea," meaning a decline in respiratory function with aging. Minor functional respiratory disability due to aging, such as that indicated by a modified Medical Research Council level 1 (troubled by shortness of breath when hurrying or walking straight up hill), is an indicator of presbypnea. We also define sarcopenic respiratory disability as "a disability with deteriorated respiratory function that results from respiratory sarcopenia." Sarcopenic respiratory disability is diagnosed if respiratory sarcopenia is present with functional disability. Cases of respiratory sarcopenia without functional disability are diagnosed as "at risk of sarcopenic respiratory disability." Functional disability is defined as a modified Medical Research Council grade of 2 or more. Rehabilitation nutrition, treatment that combines rehabilitation and nutritional management, may be adequate to prevent and treat respiratory sarcopenia and sarcopenic respiratory disability.
Topics: Aging; Female; Frailty; Humans; Male; Muscle Strength; Respiratory Muscles; Sarcopenia
PubMed: 33786569
DOI: 10.1007/s12603-021-1587-5 -
Clinical Rehabilitation Jan 2022To compare the one-year postoperative outcomes of anti-gravity treadmill rehabilitation with those of standard rehabilitation in patients with ankle or tibial plateau... (Randomized Controlled Trial)
Randomized Controlled Trial
Anti-gravity treadmill rehabilitation improves gait and muscle atrophy in patients with surgically treated ankle and tibial plateau fractures after one year: A randomised clinical trial.
OBJECTIVE
To compare the one-year postoperative outcomes of anti-gravity treadmill rehabilitation with those of standard rehabilitation in patients with ankle or tibial plateau fractures.
DESIGN
An open-label prospective randomised study.
SETTING
Three trauma centres.
SUBJECTS
Patients were randomised into the intervention (anti-gravity treadmill) or control (standard protocol) rehabilitation group.
MAIN MEASURES
The primary endpoint was changes in the Foot and Ankle Outcome Score for ankle fractures and Knee Injury and Osteoarthritis Outcome Score for tibial plateau fractures from baseline to 12 months after operation. Secondary endpoints were the subscores of these scores, muscle atrophy (leg circumference at 20 cm above and 10 cm below the knee joint) and the Dynamic Gait Index.
RESULTS
Initially, 73 patients (37 vs 36) underwent randomisation. After 12 months, 29 patients in the intervention group and 24 patients in the control group could be analysed. No significant difference was noted in the Foot and Ankle Outcome Score (80.8 ± 18.4 and 78.4 ± 21.1) and Knee Injury and Osteoarthritis Outcome Score (84.8 ± 15.2 and 81.7 ± 17.0). The change in the Dynamic Gait Index from 12 weeks to 12 months differed significantly between the groups ( = 0.04). Patients with tibial plateau fractures had a 3 cm wider thigh circumference in the intervention group than those in the control group (95% confidence interval: -0.2 to 6.3 cm, = 0.08).
CONCLUSION
One year after surgery, patients who had undergone anti-gravity treadmill rehabilitation showed better gait than patients in the control group, and those with tibial plateau fractures had less muscle atrophy.
Topics: Ankle; Gait; Humans; Muscular Atrophy; Prospective Studies; Tibial Fractures; Treatment Outcome
PubMed: 34355605
DOI: 10.1177/02692155211037148 -
The Journal of Pathology Apr 2022Benign prostatic hyperplasia (BPH) is a progressive expansion of peri-urethral prostate tissue common in aging men. Patients with enlarged prostates are treated with...
Benign prostatic hyperplasia (BPH) is a progressive expansion of peri-urethral prostate tissue common in aging men. Patients with enlarged prostates are treated with 5-alpha reductase inhibitors (5ARIs) to shrink prostate volume by blocking the conversion of testosterone to dihydrotestosterone (DHT). A reduction in DHT levels can elicit atrophy and apoptosis of prostate secretory luminal cells, which results in a favorable clinical response characterized by improved lower urinary tract symptoms. However, the histologic response to 5ARI treatment is often heterogeneous across prostate acini and lower urinary tract symptoms can persist to require surgical intervention. We used two spatial profiling approaches to characterize gene expression changes across histologically normal and atrophied regions in prostates from 5ARI-treated men. Objective transcriptomic profiling using the Visium spatial gene expression platform showed that 5ARI-induced atrophy of prostate luminal cells correlated with reduced androgen receptor signaling and increased expression of urethral club cell genes including LTF, PIGR, OLFM4, SCGB1A1, and SCGB3A1. Prostate luminal cells within atrophied acini adapted to decreased DHT conditions by increasing NF-κB signaling and anti-apoptotic BCL2 expression, which may explain their survival. Using GeoMx digital spatial profiling with a probe set to assess ~18 000 RNA targets, we confirmed that atrophied acini expressing SCGB3A1 displayed higher levels of club cell markers compared with histologically normal acini with NKX3-1 expression. In addition, club-like cells within regions of 5ARI-induced atrophy closely resembled true club cells from the prostatic urethra. A comparison of histologically normal regions from 5ARI-treated men and histologically normal regions from untreated men revealed few transcriptional differences. Taken together, our results describe a heterogeneous response to 5ARI treatment where cells in atrophied acini undergo an adaptation from a prostate secretory luminal to a club cell-like state in response to 5ARI treatment. © 2021 The Pathological Society of Great Britain and Ireland.
Topics: 5-alpha Reductase Inhibitors; Atrophy; Dihydrotestosterone; Humans; Lower Urinary Tract Symptoms; Male; Prostate; Prostatic Hyperplasia
PubMed: 34928497
DOI: 10.1002/path.5857 -
Journal of Cachexia, Sarcopenia and... Aug 2020Sarcopenia causes several adverse events in elderly people. Muscle fibre atrophy and interstitial fibrosis are the main histopathological changes in sarcopenia and...
BACKGROUND
Sarcopenia causes several adverse events in elderly people. Muscle fibre atrophy and interstitial fibrosis are the main histopathological changes in sarcopenia and account for decreased muscle function. Tribbles homologue 3 (TRB3) was previously reported to exhibit age-related expression and play a vital role in cell proliferation, differentiation, and fibrosis. We aimed to investigate how TRB3 affects sarcopenia.
METHODS
Wild-type and TRB3 knockout C57/BL6J mice were randomly divided into young and old groups. Exercise capacity was evaluated, and single-muscle function was detected by electrophysiological techniques, after which the mice were sacrificed to collect their gastrocnemius muscles for assessment of atrophy and fibrosis by histopathological and molecular biological methods. TRB3 expression, autophagy level, and MAPK signalling pathway activity were evaluated through western blotting. The interaction of TRB3 with P62 and the association between TRB3 and the MAPK signalling pathway were detected by co-immunoprecipitation.
RESULTS
In aged mice, exercise capacity and cross-sectional area of skeletal muscle fibres were decreased significantly, whereas TRB3, atrophy-related markers atrogin 1 and MuRF 1, and interstitial fibrosis, including collagen volume fraction, contents of collagens I and III, and ratio of collagens I to III, were increased significantly (P < 0.05 for all). Following TRB3 knockout, the cross-sectional area of muscle fibres, mainly fast fibres, was elevated (P < 0.05 for both), the atrogin 1 expression was decreased (P = 0.0163), and the corresponding tetanic force of fast muscles was increased (P = 0.0398). Conversely, interstitial fibrosis was substantially decreased and exercise capacity was significantly increased in the knockout mice. In terms of the underlying mechanisms, the autophagy receptor p62 was markedly increased and the MAPK signalling pathway was activated in aged skeletal muscles, which might be attributed to the interaction of TRB3 with p62 and MAPKKs, including MEK1/MEK2, MEK3/MEK6, and MEK4/MKK4. Notably, TRB3 knockout reduced the accumulation of p62 and LC3 (P < 0.05 for both), decreased the phosphorylation of JNK (P = 0.0015), and increased p38 phosphorylation (P = 0.0021).
CONCLUSIONS
TRB3 knockout in mice attenuated muscle fibre atrophy and reduced skeletal muscle fibrosis by increasing autophagy and inhibiting the MAPK signalling pathway. Correspondingly, in aged knockout mice, exercise capacity was improved. Interfering with TRB3 expression in aged skeletal muscles may serve as a target for the prevention and treatment of age-related sarcopenia.
Topics: Animals; Disease Models, Animal; Fibrosis; Humans; Mice; Mice, Knockout; Muscle, Skeletal; Muscular Atrophy; Sarcopenia
PubMed: 32096609
DOI: 10.1002/jcsm.12560 -
Journal of Cachexia, Sarcopenia and... Feb 2023Exercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular...
BACKGROUND
Exercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular mechanisms to alleviate sarcopenia is one of the most important steps towards understanding human aging. Although microRNAs (miRNAs) regulate muscle growth, regeneration and aging, the potential role of exercise-mediated miRNAs during the prevention and rehabilitation of skeletal muscle atrophy upon exercise interventions remains unclear.
METHODS
A miRNA profile by miRNA sequencing for gastrocnemius muscle of a 24-month-old aged male rat model mimicking the naturally aging process was established through screening the differentially expressed miRNAs (DEMs) for alleviating aging-induced skeletal muscle atrophy upon optimal exercise intervention. The screened miRNAs and hub genes, as well as biomarkers with the most significantly enriched pathways, were validated by quantitative real-time polymerase chain reaction and western blotting.
RESULTS
The sarcopenia index (SI) value and cross-sectional area (CSA) of rats from the old control (OC) group significantly decreased when compared with the youth control (YC) group (P < 0.001, P < 0.01), whereas an increased SI value and an enlarged CSA of rats from the old-aerobic exercise (OE), old-resistance exercise (OR) and old-mixed exercise (OM) groups were determined (P < 0.01, P < 0.001, P < 0.05; P < 0.01, P < 0.01, P < 0.05). Our results demonstrate that 764 known miRNAs, 201 novel miRNAs and 505 miRNA-mRNA interaction networks were identified to be related to aging-induced muscular atrophy. Among them, 13 miRNAs were differentially expressed (P < 0.05 and log |fold change| > 1) between the YC group and the OC group. Compared with the OC group, 7, 2 and 11 miRNAs were differentially expressed in the OE, OR and OM groups after exercise interventions, respectively. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the identified DEMs were primarily related to apoptosis, autophagy and the NF-κB/MuRF1 signalling pathways (P < 0.05). Meanwhile, four DEMs (miR-7a-1-3p, miR-135a-5p, miR-151-5p and miR-196b-5p), six hub genes (Ar, Igf1, Hif1a, Bdnf, Fak and Nras) and several biomarkers (LC3, Beclin1, p62, Bax, Bcl-2 and NF-κB/MuRF1) with the most significantly enriched pathways were confirmed, which may play a key role in muscular atrophy during the aging process.
CONCLUSIONS
These findings are closely correlated with the progression of sarcopenia and could act as potential biomarkers for the diagnosis and interventional monitoring of aging-induced skeletal muscle atrophy.
Topics: Animals; Male; Rats; Aging; Biomarkers; MicroRNAs; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Sarcopenia; Physical Conditioning, Animal
PubMed: 36457259
DOI: 10.1002/jcsm.13137 -
Nutrients Jul 2022Sarcopenia refers to a decline in muscle mass and strength with age, causing significant impairment in the ability to carry out normal daily functions and increased risk...
Sarcopenia refers to a decline in muscle mass and strength with age, causing significant impairment in the ability to carry out normal daily functions and increased risk of falls and fractures, eventually leading to loss of independence. Maintaining protein homeostasis is an important factor in preventing muscle loss, and the decrease in muscle mass is caused by an imbalance between anabolism and catabolism of muscle proteins. Although β-sitosterol has various effects such as anti-inflammatory, protective effect against nonalcoholic fatty liver disease (NAFLD), antioxidant, and antidiabetic activity, the mechanism of β-sitosterol effect on the catabolic pathway was not well known. β-sitosterol was assessed in vitro and in vivo using a dexamethasone-induced muscle atrophy mice model and C2C12 myoblasts. β-sitosterol protected mice from dexamethasone-induced muscle mass loss. The thickness of gastrocnemius muscle myofibers was increased in dexamethasone with the β-sitosterol treatment group (DS). Grip strength and creatine kinase (CK) activity were also recovered when β-sitosterol was treated. The muscle loss inhibitory efficacy of β-sitosterol in dexamethasone-induced muscle atrophy in C2C12 myotube was also verified in C2C12 myoblast. β-sitosterol also recovered the width of myotubes. The protein expression of muscle atrophy F-box (MAFbx) was increased in dexamethasone-treated animal models and C2C12 myoblast, but it was reduced when β-sitosterol was treated. MuRF1 also showed similar results to MAFbx in the mRNA level of C2C12 myotubes. In addition, in the gastrocnemius and tibialis anterior muscles of mouse models, Forkhead Box O1 (FoxO1) protein was increased in the dexamethasone-treated group (Dexa) compared with the control group and reduced in the DS group. Therefore, β-sitosterol would be a potential treatment agent for aging sarcopenia.
Topics: Animals; Dexamethasone; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Transcription Factors; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Sarcopenia; Sitosterols; Ubiquitin-Protein Ligases
PubMed: 35889851
DOI: 10.3390/nu14142894