Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness
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PROVIDER: PRJNA482398 | ENA |
REPOSITORIES: ENA
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Project description:The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre‐)frail older adults. Additionally, we examine the effect of resistance‐type exercise training on the muscle transcriptome in healthy older subjects and (pre‐)frail older adults. Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow‐up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance‐type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week. At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism, and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = −0.73). Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance‐type exercise training. Some age‐related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance‐type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re‐innervation in ageing muscle.
2018-07-24 | GSE117525 | GEO
Project description:BackgroundThe skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre-)frail older adults. Additionally, we examine the effect of resistance-type exercise training on the muscle transcriptome in healthy older subjects and (pre-)frail older adults.MethodsBaseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow-up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance-type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week.ResultsAt baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism ,and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = -0.73).ConclusionsOur data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance-type exercise training. Some age-related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance-type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re-innervation in ageing muscle.
| S-EPMC4863830 | biostudies-literature
Project description:Radiotherapy (RT) reduces the risk of cancer recurrence and death, while accompanied by multiple side effects including muscle weakness, seriously affects the life quality of patients. However, the underlying mechanism is not well defined. Here, we identify cancer cells secrete more spermidine synthase (SRM) protein through small extracellular vesicles (sEVs) to trigger skeletal muscle weakness upon RT. Mechanistically, RT-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of SRM protein, facilitating SRM package into EVs from primary tumor. Circulating SRM proteins enhance spermidine accumulation in skeletal muscle and type I collagen fibers biosynthesis in an eIF5A-dependent manner. Deposition of randomly aligned collogen fibers induced by SRM+ EVs results in skeletal muscle fibrosis and weakness, as well as bone matrix loss. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon RT, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of RT-mediated muscle weakness when combined with losartan treatment.
2025-04-03 | GSE285652 | GEO
Project description:Muscle wasting and weakness are important clinical problems that limit mobility and independence, shortening health span and increasing physical disability risk. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. Klotho-deficient mice showed impaired muscle contractility, with reduced twitch force, torque, and contraction-relaxation rates. RNA-sequencing revealed upregulation of synaptic and fetal sarcomeric genes, prompting us to examine muscle innervation. Klotho-deficiency led to neuromuscular junction remodeling, myofiber denervation, and functional motor unit loss. Loss of motor units correlated with absolute torque. Collectively, these findings reveal a novel mechanism through which Klotho-deficiency disrupts muscle synapses and motor unit connectivity, likely influences muscle wasting and weakness.
2025-09-03 | GSE302925 | GEO
Project description:Nr2f6 electroporation in tibialis anterior promotes muscle weakness
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Project description:Retinoid X receptor (RXR)-gamma is a nuclear receptor-type transcription factor expressed mostly in the skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXR-gamma in the skeletal muscle (RXR-gamma mice), which showed lower blood glucose than the control mice. We used microarrays to investigate their glucose metabolism gene expression change. RNA was isolated from the skeletal muscle of sex- and age-matched RXR-gamma mice and non-transgenic control mice (females at 4 months of age, five samples from each group were combined). Each of the combined samples of the two groups was hybridized to the Affymetrix MG430 microarray.
2011-04-08 | E-GEOD-28447 | biostudies-arrayexpress
Project description:Retinoid X receptor (RXR)-gamma is a nuclear receptor-type transcription factor expressed mostly in the skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXR-gamma in the skeletal muscle (RXR-gamma mice), which showed lower blood glucose than the control mice. We used microarrays to investigate their glucose metabolism gene expression change.
2011-04-08 | GSE28447 | GEO
Project description:ICU acquired weakness (ICUAW) is a complication of critical illness characterized by structural and functional impairment of skeletal muscle that may persist for years after ICU discharge with many survivors developing protracted courses with few regaining functional independence. Elucidating molecular mechanisms underscoring sustained ICUAW is crucial to understanding outcomes linked to different morbidity trajectories as well as for the development of novel therapies. Quadriceps muscle biopsies and functional measures of muscle strength and mass were obtained at 7 days and 6 months post-ICU discharge from a cohort of ICUAW patients. Unsupervised co-expression network analysis of transcriptomic profiles identified discrete modules of co-expressed genes associated with the degree of muscle weakness and atrophy in early and sustained ICUAW. Modules were enriched for genes involved in skeletal muscle regeneration and extracellular matrix deposition. Collagen deposition in persistent ICUAW was confirmed by histochemical stain. Modules were further validated in an independent cohort of critically ill patients with sepsis-induced multi-organ failure and a porcine model of ICUAW, demonstrating disease-associated conservation across species and peripheral muscle type. Our findings provide a pathomolecular basis for sustained ICUAW, implicating aberrant expression of distinct skeletal muscle structural and regenerative genes in early and persistent ICUAW. Total RNA was extracted from approximately 200mg of quadriceps muscle (vastus lateralis) tissue in patients with Intensive care unit (ICU) acquired weakness (ICUAW) at day 7 post-ICU discharge (D7) and month 6 post-ICU discharge (M6), and from healthy controls (C)
2016-07-18 | E-GEOD-78929 | biostudies-arrayexpress
Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation. We used microarrays to gain insight into potential mechanisms of DS-associated skeletal muscle weakness. Soleus muscles were obtained from four male Ts65Dn (DS) mice and four male colony control mice. Animals were apparently healthy and approximately five months old. The muscles were harvested in the basal state under anesthesia induced by sodium pentobarbital at approximately the same time of the day.
2013-01-06 | E-GEOD-39159 | biostudies-arrayexpress
Project description:Myotonic dystrophes (DM), the most common adult muscular dystrophy, are the first recognized examples of RNA-mediated diseases in which expression of mutant RNAs containing expanded CUG or CCUG repeats interfere with the splicing of other mRNAs. Using whole-genome microarrays, we found that alternative splicing of the BIN1 mRNA is altered in DM skeletal muscle tissues, resulting in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. BIN1 is involved in tubular invaginations of the plasma membrane and is essential for biogenesis of the muscle T-tubules, which are specialized skeletal muscle membrane structures essential to correct excitation-contraction (E-C) coupling. Mutations in the BIN1 gene cause centronuclear myopathy (CNM) that shares some histopathological features with DM, and both diseases are characterized by muscle weakness. Consistent with a loss-of-function of BIN1, muscle T-tubules were altered in DM patients, and membrane tubulation was restored upon expression of the correct splicing form of BIN1 in DM muscle cells. By deciphering the mechanism of BIN1 splicing mis-regulation we demonstrate that the splicing regulator, MBNL1, which is sequestered by expanded CUG and CCUG in DM, binds the BIN1 pre-mRNA and regulates directly its alternative splicing. Finally, reproducing BIN1 splicing alteration in mice is sufficient to reproduce the DM features of T-tubule alterations and muscle weakness. We propose that alteration of BIN1 alternative splicing regulation leads to muscle weakness, a predominant pathological feature of DM. Exon-Array analysis of control and CDM1 muscle primary cultures 10 days of differentiation
2011-05-26 | E-GEOD-21795 | biostudies-arrayexpress