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Frontiers in Endocrinology 2021Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging,...
Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging, injury, hormone imbalance and other catabolic conditions. Recently, exosomes were considered to regulate muscle regeneration and protein synthesis. In order to confirm the effect of BMSC-derived exosomes (BMSC-Exos) on muscle, dexamethasone-induced muscle atrophy was built both and . In the present research, BMSC-Exos attenuated the decrease of myotube diameter induced by dexamethasone, indicating that BMSC-Exos played a protective role in skeletal muscle atrophy. Further mechanism analysis exhibited that the content of miR-486-5p in C2C12 myotubes was up-regulated after treated with BMSC-Exos. Meanwhile, BMSC-Exos markedly downregulated the nuclear translocation of FoxO1, which plays an important role in muscle differentiation and atrophy. Importantly, the miR-486-5p inhibitor reversed the decreased expression of FoxO1 induced by BMSC-Exos. In animal experiments, BMSC-Exos inhibited dexamethasone-induced muscle atrophy, and miR-486-5p inhibitor reversed the protective effect of BMSC-Exos. These results indicating that BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy miR486-5p/Foxo1 Axis.
Topics: Animals; Cell Differentiation; Dexamethasone; Exosomes; Forkhead Box Protein O1; Mesenchymal Stem Cells; Mice; MicroRNAs; Muscular Atrophy; Signal Transduction
PubMed: 34659106
DOI: 10.3389/fendo.2021.681267 -
Nature Communications May 2017A number of microRNAs (miRNAs, miRs) have been shown to play a role in skeletal muscle atrophy, but their role is not completely understood. Here we show that miR-29b...
A number of microRNAs (miRNAs, miRs) have been shown to play a role in skeletal muscle atrophy, but their role is not completely understood. Here we show that miR-29b promotes skeletal muscle atrophy in response to different atrophic stimuli in cells and in mouse models. miR-29b promotes atrophy of myotubes differentiated from C2C12 or primary myoblasts, and conversely, its inhibition attenuates atrophy induced by dexamethasone (Dex), TNF-α and HO treatment. Targeting of IGF-1 and PI3K(p85α) by miR-29b is required for induction of muscle atrophy. In vivo, miR-29b overexpression is sufficient to promote muscle atrophy while inhibition of miR-29b attenuates atrophy induced by denervation and immobilization. These data suggest that miR-29b contributes to multiple types of muscle atrophy via targeting of IGF-1 and PI3K(p85α), and that suppression of miR-29b may represent a therapeutic approach for muscle atrophy induced by different stimuli.
Topics: Animals; Base Sequence; Cell Line; Gene Expression Regulation; Insulin-Like Growth Factor I; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; MicroRNAs; Muscular Atrophy; Phosphatidylinositol 3-Kinases; Rats, Sprague-Dawley; Up-Regulation; YY1 Transcription Factor
PubMed: 28541289
DOI: 10.1038/ncomms15201 -
Advanced Science (Weinheim,... Jun 2023Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are...
Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.
Topics: Mice; Animals; RNA, Circular; Muscular Atrophy; DNA-Binding Proteins; DNA, Mitochondrial; Mitochondria
PubMed: 37088818
DOI: 10.1002/advs.202206732 -
Journal of Cachexia, Sarcopenia and... Apr 2023Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can...
BACKGROUND
Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy.
METHODS
Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms.
RESULTS
hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO.
CONCLUSIONS
Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.
Topics: Animals; Humans; Mice; AMP-Activated Protein Kinases; Autophagy; Autophagy-Related Protein-1 Homolog; Diabetes Mellitus, Type 2; Exosomes; Intracellular Signaling Peptides and Proteins; Mesenchymal Stem Cells; Muscular Atrophy; Obesity
PubMed: 36708027
DOI: 10.1002/jcsm.13177 -
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 -
Journal of Cachexia, Sarcopenia and... Jun 2022Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease...
BACKGROUND
Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin-mediated mitophagy, a mitochondrion-selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD-related sarcopenia.
METHODS
The involvement of Parkin-mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS-exposure model using Parkin mice, and human muscle samples from patients with COPD-related sarcopenia.
RESULTS
Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin-mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF-1)-mediated myosin heavy chain (MHC) degradation. Parkin mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF-1 expression (P < 0.01) compared with wild-type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD-related sarcopenia exhibited significantly reduced Parkin but increased MuRF-1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation-induced muscle contraction prevented CSE-induced MHC reduction by maintaining Parkin levels in myotubes.
CONCLUSIONS
Taken together, COPD-related sarcopenia can be attributed to insufficient Parkin-mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF-1 activation, which may be at least partly preventable through optimal physical exercise.
Topics: Animals; Humans; Mice; Mice, Inbred C57BL; Mitophagy; Muscular Atrophy; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Sarcopenia; Ubiquitin-Protein Ligases
PubMed: 35373498
DOI: 10.1002/jcsm.12988 -
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 -
BMC Musculoskeletal Disorders Aug 2022Extensive muscle atrophy is a common occurrence in orthopaedics patients who are bedridden or immobilized. The incidence is higher in intensive care unit (ICU)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Extensive muscle atrophy is a common occurrence in orthopaedics patients who are bedridden or immobilized. The incidence is higher in intensive care unit (ICU) inpatients. There is still controversy about how to use neuromuscular electrical stimulation (NMES) in ICU patients. We aim to compare the effectiveness and safety of NMES to prevent muscle atrophy in intensive care unit (ICU) patients without nerve injury.
METHODS
ICU patients without central and peripheral nerve injury were randomized into experimental group I (Exp I: active and passive activity training (APAT) + NMES treatment on the gastrocnemius and tibialis anterior muscle), experimental group II (Exp II: APAT + NMES treatment on gastrocnemius alone), and control group (Ctl: APAT alone). Changes in the strength of gastrocnemius, the ankle range of motion, and the muscle cross-section area of the lower leg were evaluated before and after the intervention. Also, changes in prothrombin time, lactic acid, and C-reactive protein were monitored during the treatment.
RESULTS
The gastrocnemius muscle strength, ankle joint range of motion, and cross-sectional muscle area of the lower leg in the three groups showed a downward trend, indicating that the overall trend of muscle atrophy in ICU patients was irreversible. The decrease in gastrocnemius muscle strength in Exp I and Exp II was smaller than that in the control group (P < 0.05), but there was no difference between Exp I and Exp II. The decrease in active ankle range of motion and cross-sectional area of the lower leg Exp I and Exp II was smaller than that in the control group (P < 0.05), and the decrease in Exp I was smaller than that of Exp II (all P < 0.05). The curative effect in Exp I was better than in Exp II. There were no significant differences in the dynamic changes of prothrombin time, lactic acid, and C-reactive protein during the three groups (P > 0.05).
CONCLUSION
In addition to early exercise training, NMES should be applied to prevent muscle atrophy for patients without nerve injury in ICU. Also, simultaneous NMES treatment on agonist/antagonist muscle can enhance the effect of preventing muscle atrophy.
TRIAL REGISTRATION
This study was prospectively registered in China Clinical Trial Registry ( www.chictr.org.cn ) on 16/05/2020 as ChiCTR2000032950.
Topics: C-Reactive Protein; Electric Stimulation Therapy; Humans; Intensive Care Units; Lactic Acid; Muscle Strength; Muscle, Skeletal; Muscular Atrophy
PubMed: 35974369
DOI: 10.1186/s12891-022-05739-2 -
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 -
F1000Research 2019It is well established that mitochondria play a critical role in the metabolic and physiological adaptation of skeletal muscle to enhanced contractile activity. Several... (Review)
Review
It is well established that mitochondria play a critical role in the metabolic and physiological adaptation of skeletal muscle to enhanced contractile activity. Several redox-sensitive signaling pathways such as PGC-1α, AMPK, IGF/Akt/mTOR, SIRT, NFκB, and FoxO are involved with extensive crosstalk to regulate vital cellular functions such as mitochondrial biogenesis, mitochondrial fusion and fission dynamics, autophagy/mitophagy, and apoptosis under altered demand and stress. However, when muscles cease contraction, such as during immobilization and denervation, mitochondria undergo a series of detrimental changes characterized by downregulation of PGC-1α and antioxidant defense, increased ROS generation, activated FoxO, NFκB, and inflammation, enhanced ubiquitination, and finally mitophagy and apoptotic cascades. The phenotypic outcome of the discord of mitochondrial homeostasis is elevated proteolysis and muscle atrophy. The demonstration that PGC-1α overexpression via transgene or DNA transfection can restore mitochondrial homeostasis and reverse myocyte atrophy supports the "mitostasis theory of muscle atrophy".
Topics: Humans; Mitochondria; Mitophagy; Muscular Atrophy; Muscular Disorders, Atrophic; Transcription Factors
PubMed: 31559011
DOI: 10.12688/f1000research.19139.1