Social participation and health in middle-aged and older empty nesters: A study on gender differences.

Background: The growing population of middle-aged and older empty nesters is characterized by poorer health, and social participation (SP) has been shown to improve this situation. However, few studies have investigated specific performance and gender differences between SP and health. The present study aims to address these issues. Methods: A total of 1207 middle-aged and older empty nesters over 45 years old were selected from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018). Random-effects analyses were used to explore the association between changes in SP (diversity, frequency, type) and changes in health status. Health status include physical health, mental health, self-reported health (SRH). Results: Female middle-aged and olderly empty nesters have significantly poorer health and participate in SP more frequently. The higher the diversity of SP, the better the health of middle-aged and olderly empty nesters, while higher frequency is beneficial to SRH. Female's participation in sports and Internet had better mental health and SRH, and mahjong helped female's mental health. Clubs are helpful for male's SRH. Conclusions: This study reveals the specifics of the association between SP and health status of middle-aged and older empty nesters. Therefore, all aspects of SP and gender differences should be taken into account when predicting and improving the health status. Help the government to better formulate policies to better cope with the increasing empty nest phenomenon and build a harmonious and stable society.

Angiogenic potential of skeletal muscle derived extracellular vesicles differs between oxidative and glycolytic muscle tissue in mice.

Skeletal muscle fibers regulate surrounding endothelial cells (EC) via secretion of numerous angiogenic factors, including extracellular vesicles (SkM-EV). Muscle fibers are broadly classified as oxidative (OXI) or glycolytic (GLY) depending on their metabolic characteristics. OXI fibers secrete more pro-angiogenic factors and have greater capillary densities than GLY fibers. OXI muscle secretes more EV than GLY, however it is unknown whether muscle metabolic characteristics regulate EV contents and signaling potential. EVs were isolated from primarily oxidative or glycolytic muscle tissue from mice. MicroRNA (miR) contents were determined and endothelial cells were treated with OXI- and GLY-EV to investigate angiogenic signaling potential. There were considerable differences in miR contents between OXI- and GLY-EV and pathway analysis identified that OXI-EV miR were predicted to positively regulate multiple endothelial-specific pathways, compared to GLY-EV. OXI-EV improved in vitro angiogenesis, which may have been mediated through nitric oxide synthase (NOS) related pathways, as treatment of endothelial cells with a non-selective NOS inhibitor abolished the angiogenic benefits of OXI-EV. This is the first report to show widespread differences in miR contents between SkM-EV isolated from metabolically different muscle tissue and the first to demonstrate that oxidative muscle tissue secretes EV with greater angiogenic signaling potential than glycolytic muscle tissue.

PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors.

Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.

Association of Public Sports Space Perception with Health-Related Quality of Life in Middle-Aged and Older Adults-Evidence from a Survey in Shandong, China.

Creating a healthy living environment for middle-aged and older adults is a key strategy for countries to address the aging challenge, but the effects of such an environment on the health-related quality of life (HRQoL) of middle-aged and older adults remain underexplored. This study aimed to examine the link between public sports facilities and the HRQoL of middle-aged and older adult residents in communities. A total of 1169 respondents (average age: 66.84; male: 46.19%) were selected from the Shandong, China. This study measured respondents 'physical activity (PA) using the International Physical Activity Questionnaire, the HRQoL of respondents using the 36-item Short Form Health Survey, and the Public Sports Space Perception Scale for respondents' public sports space perception. Correlation analysis and logistic regression analysis were employed to test the relationship among public sports space perception, physical activity (PA), and HRQoL. The mediating role of PA was conducted using the PROCESS macro for SPSS. The results revealed that public sports space perception only influenced the HRQoL of middle-aged and older adults through light-intensity PA (PCS: B = 0.09, 95% CI 0.01, 0.03; MCS: B = 0.02, 95% CI 0.01, 0.05) among light-intensity PA, moderate-intensity PA, vigorous-intensity PA., and this mediation model varied across different age groups of middle-aged and older adults. Moreover, digital inclusion only moderated the psychological aspect of HRQoL of middle-aged and older adults (p < 0.05). This study provided empirical evidence for enhancing the HRQoL of middle-aged and older adults and offered useful insights for the planning and design of public sports facilities and the formulation of health management policies for middle-aged and older adults.

The Role of Proton-Coupled Amino Acid Transporter 2 (SLC36A2) in Cold-Induced Thermogenesis of Mice.

Brown adipocytes mainly utilize glucose and fatty acids to produce energy, which play key roles in thermogenesis. Furthermore, brown adipocytes also utilize other substrates, such as amino acids, for energy expenditure in various conditions. Here, we report the new physiological roles of proton-coupled amino acid transporters, SLC36A2 and SLC36A3, on global energy metabolism. The relative mRNA expression levels of both Slc36a2 and Slc36a3 were all highest in brown adipose tissue. We then generated global Slc36a2 and Slc36a3 knockout mice to investigate their functions in metabolism. Neither loss of Slc36a2 nor Slc36a3 affected the body weight and body composition of the mice. Slc36a2 knockout mice exhibited increased oxygen consumption during the daytime. After cold treatment, inhibition of Slc36a2 significantly decreased the mass of brown adipose tissue compared to wildtype mice, while it lowered the expression level of Cpt1a. Moreover, the serum lipid levels and liver mass were also decreased in Slc36a2 knockout mice after cold treatment. On the contrary, Slc36a3 knockout impaired glucose tolerance and up-regulated serum LDL-cholesterol concentration. Thus, SLC36A2 and SLC36A3 play central and different roles in the energy metabolism of the mice.

PRMT5 links lipid metabolism to contractile function of skeletal muscles.

Skeletal muscle plays a key role in systemic energy homeostasis besides its contractile function, but what links these functions is poorly defined. Protein Arginine Methyl Transferase 5 (PRMT5) is a well-known oncoprotein but also expressed in healthy tissues with unclear physiological functions. As adult muscles express high levels of Prmt5, we generated skeletal muscle-specific Prmt5 knockout (Prmt5MKO ) mice. We observe reduced muscle mass, oxidative capacity, force production, and exercise performance in Prmt5MKO mice. The motor deficiency is associated with scarce lipid droplets in myofibers due to defects in lipid biosynthesis and accelerated degradation. Specifically, PRMT5 deletion reduces dimethylation and stability of Sterol Regulatory Element-Binding Transcription Factor 1a (SREBP1a), a master regulator of de novo lipogenesis. Moreover, Prmt5MKO impairs the repressive H4R3 symmetric dimethylation at the Pnpla2 promoter, elevating the level of its encoded protein ATGL, the rate-limiting enzyme catalyzing lipolysis. Accordingly, skeletal muscle-specific double knockout of Pnpla2 and Prmt5 normalizes muscle mass and function. Together, our findings delineate a physiological function of PRMT5 in linking lipid metabolism to contractile function of myofibers.

Dynamic Correlation Adjacency-Matrix-Based Graph Neural Networks for Traffic Flow Prediction.

Modeling complex spatial and temporal dependencies in multivariate time series data is crucial for traffic forecasting. Graph convolutional networks have proved to be effective in predicting multivariate time series. Although a predefined graph structure can help the model converge to good results quickly, it also limits the further improvement of the model due to its stationary state. In addition, current methods may not converge on some datasets due to the graph structure of these datasets being difficult to learn. Motivated by this, we propose a novel model named Dynamic Correlation Graph Convolutional Network (DCGCN) in this paper. The model can construct adjacency matrices from input data using a correlation coefficient; thus, dynamic correlation graph convolution is used for capturing spatial dependencies. Meanwhile, gated temporal convolution is used for modeling temporal dependencies. Finally, we performed extensive experiments to evaluate the performance of our proposed method against ten existing well-recognized baseline methods using two original and four public datasets.

The Effect of Activity Participation in Middle-Aged and Older People on the Trajectory of Depression in Later Life: National Cohort Study.

BACKGROUND: More activity participation is an important means of handling depression and promoting positive aging, but the impact of changes in activity participation on the developmental trajectory of depression has not been fully studied. OBJECTIVE: The purpose of this study is to study the relationship between current activity participation and depression in middle-aged and older people (≥45 years old) and the relationship between activity participation and the developmental trajectory of depression in later life in China. METHODS: This study used data from the China Health and Retirement Longitudinal Study (CHARLS) across 7 years and included a total of 4818 middle-aged and older people (≥45 years old). Controlling for relevant control variables, the latent growth curve model and the cross-lag model were used to assess the effect of changes in activity participation on the depression trajectory in later life and the main lag relationship between activity participation and depression. Activity participation as well as depression were measured using the self-reported activity and health status based on the CHARLS questionnaire. RESULTS: Among the 4818 respondents, the mean values of physical activity participation, social leisure activity participation, and depression ranged from 76.98 (SD 15.16) to 83.95 (SD 5.72), from 7.43 (SD 8.67) to 9.25 (SD 10.16), and from 7.61 (SD 5.72) to 8.82 (SD 6.51), respectively. Our findings revealed that activity participation could be related to depression. Physical activity participation predicted initial depression (ß=-0.631, P<.001) and its trajectory (ß=0.461, P<.001). However, social leisure activity participation predicted initial depression (ß=-0.223, P<.001) but did not predict its trajectory (ß=0.067, P=.159). Finally, cross-lag regression analysis further demonstrated the predictive effect of activity participation on depression. CONCLUSIONS: This study demonstrates the prediction of activity participation for future depression in the Chinese middle-aged and older populations. The data showed that activity participation is significantly associated with changes in depression and future depression among middle-aged and older people in China. The Chinese government should encourage middle-aged and older people to participate in various activities, which can effectively prevent the aggravation of depression and also have a positive significance for positive aging.

Hepatic Acat2 overexpression promotes systemic cholesterol metabolism and adipose lipid metabolism in mice.

AIMS/HYPOTHESIS: Acetyl coenzyme A acetyltransferase (ACAT), also known as acetoacetyl-CoA thiolase, catalyses the formation of acetoacetyl-CoA from acetyl-CoA and forms part of the isoprenoid biosynthesis pathway. Thus, ACAT plays a central role in cholesterol metabolism in a variety of cells. Here, we aimed to assess the effect of hepatic Acat2 overexpression on cholesterol metabolism and systemic energy metabolism. METHODS: We generated liver-targeted adeno-associated virus 9 (AAV9) to achieve hepatic Acat2 overexpression in mice. Mice were injected with AAV9 through the tail vein and subjected to morphological, physiological (body composition, indirect calorimetry, treadmill, GTT, blood biochemistry, cardiac ultrasonography and ECG), histochemical, gene expression and metabolomic analysis under normal diet or feeding with high-fat diet to investigate the role of ACAT2 in the liver. RESULTS: Hepatic Acat2 overexpression reduced body weight and total fat mass, elevated the metabolic rate, improved glucose tolerance and lowered the serum cholesterol level of mice. In addition, the overexpression of Acat2 inhibited fatty acid, glucose and ketone metabolic pathways but promoted cholesterol metabolism and changed the bile acid pool and composition of the liver. Hepatic Acat2 overexpression also decreased the size of white adipocytes and promoted lipid metabolism in white adipose tissue. Furthermore, hepatic Acat2 overexpression protected mice from high-fat-diet-induced weight gain and metabolic defects CONCLUSIONS/INTERPRETATION: Our study identifies an essential role for ACAT2 in cholesterol metabolism and systemic energy expenditure and provides key insights into the metabolic benefits of hepatic Acat2 overexpression. Thus, adenoviral Acat2 overexpression in the liver may be a potential therapeutic tool in the treatment of obesity and hypercholesterolaemia.

Effects of pain and depression on the relationship between household solid fuel use and disability among middle-aged and older adults.

Household air pollution (HAP) is suggested to increases people's risk of disability, but mediating mechanisms between HAP and disability remains under-investigated. The aim of this study was to investigate the underlying mechanisms between household air pollution and disability in middle-aged and older adults (i.e., older than 45 years) using a nationally representative prospective cohort. In total, 3754 middle-aged and older adults were selected from the China Health and Retirement Longitudinal Study. Correlation analysis and logistic regression analysis were employed to estimate the association between HAP, pain, depression and disability. Finally, three significant mediation pathways through which HAP directly impacts disability were found: (1) pain (B = 0.09, 95% CI 0.01, 0.02), accounting for 15.25% of the total effect; (2) depression (B = 0.07, 95% CI 0.004, 0.02), accounting for 11.86% of the total effect; (3) pain and depression (B = 0.04, 95% CI 0.003, 0.01), accounting for 6.78% of the total effect. The total mediating effect was 33.89%. This study clarified that HAP can indirectly affect disability through the respective and serial mediating roles of pain and depression. These findings potentially have important implications for national strategies concerning the widespread use of clean fuels by citizens.

The relationship between gender, marital status and depression among Chinese middle-aged and older people: Mediation by subjective well-being and moderation by degree of digitization.

The purposes of this study were to investigate the effects of gender and marital status on depression among middle-aged and older people in China, and to explore the mediating effect of subjective well-being and the moderating effect of degree of digitization in the relationship between subjective well-being and depression. A total of 15,586 Chinese middle-aged and older people (≥ 45 years old) were included in the study using data from the 2018 China Health and Retirement Longitudinal Survey (CHARLS). T-test, ANOVA, hierarchical regression and Bootstrap methods were adopted to test the mediating role of subjective well-being and the moderating role of degree of digitization. The results showed that middle-aged and older women were more likely to suffer from depression than men, and married middle-aged and older people were less likely to be depressed than those who were separated or divorced, widowed and never married. Subjective well-being partially mediated the relationship between gender and depression, and masked the relationship between marital status and depression, and all five dimensions it contains also played a mediating role. Degree of digitization moderated the effect of subjective well-being on depression. Simple slope tests indicated that the effect of subjective well-being on depression increased as degree of digitization increased. In conclusion, to address the mental health problems of middle-aged and older people brought about by the ageing and digital society, we should start by improving their subjective well-being and promoting their integration into the digital society.

Longitudinal Relationship between Cognitive Function and Health-Related Quality of Life among Middle-Aged and Older Patients with Diabetes in China: Digital Usage Behavior Differences.

BACKGROUND: Cognitive function and health-related quality of life (HRQoL) are important issues in diabetes care. According to the China Association for Aging, it is estimated that by 2030, the number of elderly people with dementia in China will reach 22 million. The World Health Organization reports that by 2044, the number of people with diabetes in China is expected to reach 175 million. METHODS: Cohort analyses were conducted based on 854 diabetic patients aged ≥45 years from the third (2015) and fourth (2018) survey of the China Health and Retirement Longitudinal Study (CHARLS). Correlation analysis, repeated-measures variance analysis, and cross-lagged panel models were used to measure the difference in digital usage behavior in the established relationship. RESULTS: The results show that the cognitive function of middle-aged and older diabetic patients is positively correlated with HRQoL. HRQoL at T1 could significantly predict cognitive function at T2 (PCS: B = 0.12, p < 0.01; MCS: B = 0.14, p < 0.01). This relationship is more associated with individual performance than digital usage behavior. CONCLUSIONS: Unidirectional associations may exist between cognitive function and HRQoL among middle-aged and older Chinese diabetes patients. In the future, doctors and nurses can recognize the lowering of self-perceived HRQoL of middle-aged and older diabetic patients, and thus draw more attention to their cognitive function, in turn strengthening the evaluation, detection, and intervention of their cognitive function.

Effects of exercise combined with diet intervention on body composition and serum biochemical markers in adolescents with obesity: a systematic review and meta-analysis.

BACKGROUND: This systematic review aims to evaluate the effects of exercise combined with diet (ECWD), exercise alone, diet alone, and no intervention on body composition and serum biochemical markers in adolescents with obesity to provide reference for solving the metabolic disorders of adolescents caused by obesity. CONTENTS: Studies published before January 5, 2021 were retrieved from PubMed, Web of Science, Ovid, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang data, VIP database, and SinoMed. Randomized controlled trials with an age between 10 and 20 years, body mass index (BMI) ≥28 kg/m2 or ≥95th percentiles, no history of endocrine and metabolic diseases, heart disease, hematologic disease, and so on before the trial were included. SUMMARY: Fifteen of the 50,155 studies met the criteria. Meta-analysis showed that ECWD was more effective in reducing BMI (kg/m2) (-2.45 kg/m2, 95% CI: -3.06; -1.85) and fat thickness of back (-13.77 mm, 95% CI: -15.92; -11.62), abdomen (-11.56 mm, 95% CI: -14.04; -9.09), and upper arm (-14.81 mm, 95% CI: -16.74; -12.89) than other interventions; in reducing body fat (-7.03 kg, 95% CI: -9.77; -4.29) and thigh circumference (-4.05 cm, 95% CI: -5.58; -2.52), ECWD and diet alone were more effective than exercise alone; ECWD and exercise alone were more effective in reducing waist circumference (-6.05 cm, 95% CI: -8.37; -3.72), waist-to-hip ratio (WHR; -0.06, 95% CI: -0.11; -0.01), upper arm circumference (-2.57 cm, 95% CI: -3.70; -1.45), triglycerides (TG; -0.30 mmol/L, 95% CI: -0.45; -0.14), total cholesterol (TC; -0.30 mmol/L, 95% CI: -0.59; -0.01), and low density lipoprotein (LDL; -0.22 mmol/L, 95% CI: -0.40; -0.04) than diet alone. ECWD also had effects on tumor necrosis factor-α (TNF-α), interleukin-6, leptin, and so on. OUTLOOK: ECWD is more effective than exercise alone, diet alone, or no intervention in solving the problems of body shape and metabolic disorder of adolescents with obesity.

Proto-oncogene FAM83A contributes to casein kinase 1-mediated mitochondrial maintenance and white adipocyte differentiation.

Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid to knockdown Fam83a (ATS/sg-FAM83A) in white adipose tissue in mice, which resulted in reduced white adipose tissue mass, smaller adipocytes, and mitochondrial damage that was aggravated by a high-fat diet. In cultured 3T3-L1 adipocytes, we found loss or knockdown of Fam83a significantly repressed lipid droplet formation and downregulated the expression of lipogenic genes and proteins. Furthermore, inhibition of Fam83a decreased mitochondrial ATP production through blockage of the electron transport chain, associated with enhanced apoptosis. Mechanistically, we demonstrate FAM83A interacts with casein kinase 1 (CK1) and promotes the permeability of the mitochondrial outer membrane. Furthermore, loss of Fam83a in adipocytes hampered the formation of the TOM40 complex and impeded CK1-driven lipogenesis. Taken together, these results establish FAM83A as a critical regulator of mitochondria maintenance during adipogenesis.

ACSS3 in brown fat drives propionate catabolism and its deficiency leads to autophagy and systemic metabolic dysfunction.

Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA synthetase short-chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3-/- ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high-fat diet (HFD). Intriguingly, Acss3-/- or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3-/- mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3-/- mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.

Regulation of apoptosis by Pacific oyster Crassostrea gigas reveals acclimation strategy to CO2 driven acidification.

Ocean acidification (OA) has posed formidable threats to marine calcifiers. In response to elevated CO2 levels, marine calcifiers have developed multiple strategies to survive, such as taking advantage of apoptosis, but its regulation mechanism remains largely unknown. Here, we used the Pacific oyster Crassostrea gigas as model to understand the apoptotic responses and regulation mechanism at short- (7 d) to long-term (56 d) CO2 exposure (pH = 7.50). The apoptosis of hemocytes was significantly induced after short-term treatment (7-21 d) but was suppressed under long-term CO2 exposure (42-56 d). Similarly, caspase-3 and caspase-9 were also increased post short-term exposure and fell back to normal levels after long-term exposure. These data together indicated diverse regulation mechanisms of apoptosis through different exposure periods. Through analysis of the B-cell lymphoma 2 (Bcl-2) family mitochondrial apoptosis regulators, we showed that only CgBcl-XL's expression kept at high levels after 42- and 56-day CO2 exposure. CgBcl-XL shared sequence, and structural similarity with its mammalian counterpart, and knockdown of CgBcl-XL in hemocytes via RNA interference promoted apoptosis. The protein level of CgBcl-XL was significantly increased after long-term CO2 exposure (28-56 d), and its distribution in hemocytes became more concentrated and dense. Therefore, CgBcl-XL serves as an essential anti-apoptotic protein for tipping the balance of cell apoptosis, which may play a key role in survival under long-term CO2 exposure. These results reveal a potential adaptation strategy of oysters towards OA and the variable environment changes through the modulation of apoptosis.

Reduced electron transport chain complex I protein abundance and function in Mfn2-deficient myogenic progenitors lead to oxidative stress and mitochondria swelling.

Mitochondrial remodeling through fusion and fission is crucial for progenitor cell differentiation but its role in myogenesis is poorly understood. Here, we characterized the function of mitofusin 2 (Mfn2), a mitochondrial outer membrane protein critical for mitochondrial fusion, in muscle progenitor cells (myoblasts). Mfn2 expression is upregulated during myoblast differentiation in vitro and muscle regeneration in vivo. Targeted deletion of Mfn2 gene in myoblasts (Mfn2MKO ) increases oxygen-consumption rates (OCR) associated with the maximal respiration and spare respiratory capacity, and increased levels of reactive oxygen species (ROS). Skeletal muscles of Mfn2MKO mice exhibit robust mitochondrial swelling with normal mitochondrial DNA content. Additionally, mitochondria isolated from Mfn2MKO muscles have reduced OCR at basal state and for complex I respiration, associated with decreased levels of complex I proteins NDUFB8 (NADH ubiquinone oxidoreductase subunit B8) and NDUFS3 (NADH ubiquinone oxidoreductase subunit S3). However, Mfn2MKO has no obvious effects on myoblast differentiation, muscle development and function, and muscle regeneration. These results demonstrate a novel role of Mfn2 in regulating mitochondrial complex I protein abundance and respiratory functions in myogenic progenitors and myofibers.

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is caused by a mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting, loss of mobility, and, ultimately, cardiorespiratory failure and premature death. Currently there is no cure for DMD. Herein, we report that skeletal muscle-specific knockout (KO) of the phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidence. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and it improves grip strength and exercise performance in mdx mice. Pten KO also reduces fibrosis and inflammation, and it ameliorates muscle pathology in mdx mice. Unbiased RNA sequencing reveals that Pten KO upregulates extracellular matrix and basement membrane components positively correlated with wound healing and suppresses negative regulators of wound healing and lipid biosynthesis, thus improving the integrity of muscle basement membrane at the ultrastructural level. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our findings provide evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

Biomimetic glycosaminoglycan-based scaffolds improve skeletal muscle regeneration in a Murine volumetric muscle loss model.

Volumetric muscle loss (VML) injuries characterized by critical loss of skeletal muscle tissues result in severe functional impairment. Current treatments involving use of muscle grafts are limited by tissue availability and donor site morbidity. In this study, we designed and synthesized an implantable glycosaminoglycan-based hydrogel system consisting of thiolated hyaluronic acid (HA) and thiolated chondroitin sulfate (CS) cross-linked with poly(ethylene glycol) diacrylate to promote skeletal muscle regeneration of VML injuries in mice. The HA-CS hydrogels were optimized with suitable biophysical properties by fine-tuning degree of thiol group substitution to support C2C12 myoblast proliferation, myogenic differentiation and expression of myogenic markers MyoD, MyoG and MYH8. Furthermore, in vivo studies using a murine quadriceps VML model demonstrated that the HA-CS hydrogels supported integration of implants with the surrounding host tissue and facilitated migration of Pax7+ satellite cells, de novo myofiber formation, angiogenesis, and innervation with minimized scar tissue formation during 4-week implantation. The hydrogel-treated and autograft-treated mice showed similar functional improvements in treadmill performance as early as 1-week post-implantation compared to the untreated groups. Taken together, our results demonstrate the promise of HA-CS hydrogels as regenerative engineering matrices to accelerate healing of skeletal muscle injuries.