Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA280959 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signalâs secondary function in the activity-dependent regulation of fiber type composition. Differential gene expression between soleus and EDL muscle fibres from wildtype and Cav1.1 delta E29 mice.
2016-04-01 | E-GEOD-67803 | biostudies-arrayexpress
Project description:Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signal’s secondary function in the activity-dependent regulation of fiber type composition.
2016-04-01 | GSE67803 | GEO
Project description:This experiment was conducted to identify the mitochondrial protein changes in the presence and absence of LONP1 in skeletal muscle. The following abstract from the submitted manuscript describes the major findings of this work.Disuse-associated loss of muscle LONP1 impairs mitochondrial quality and causes reduced skeletal muscle mass and strength. Zhisheng Xu, Tingting Fu, Qiqi Guo, Danxia Zhou, Wanping Sun, Zheng Zhou, Lin Liu, Liwei Xiao, Yujing Yin, Yuhuan Jia, Xin Pan, Lei Fang, Min-sheng Zhu, Wenyong Fei, Bin Lu and Zhenji Gan. Mitochondrial proteolysis is an evolutionarily conserved quality control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a critical role in controlling mitochondrial quality as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel an intriguing link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.
2022-01-05 | PXD029722 | Pride
Project description:Skeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine if a mitochondrial myopathy is associated with adjustments in skelatal fiber type composition. These effects of drug induced mitochondrial dysfunction on skeletal muscle fiber type composition were analyzed in an animal model.
2012-10-18 | E-MEXP-3642 | biostudies-arrayexpress
Project description:Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling. Here we wanted to better elucidate the functional role of mTOR on muscle contractility. Most loss of function studies for mTOR signaling have used the drug rapamycin to inhibit some of the signaling downstream of mTOR. However, as rapamycin does not completely inhibit all mTOR signaling, we generated a double k.o. for mTOR and for the scaffold protein of mTORC1, Raptor, in skeletal muscle. We found that dk.o. mice results in a more severe phenotype compared to Raptor or mTOR deletion alone. Indeed, they display muscle weakness, increased fiber denervation, and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibers and changes in the expression levels of calcium-related genes, like Serca1 and Casq1. Indeed, dk.o. mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes are linked to sarcomere organization, like Tcap and Fhod3. These results suggest a key role for mTOR signaling in maintaining a proper fiber relaxation in skeletal muscle.
2022-10-19 | GSE215314 | GEO
Project description:This experiment was conducted to identify target genes of the microRNA-499 in skeletal muscle of transgenic mice that overexpressed miR-499. The following abstract from the submitted manuscript describes the major findings of this work. Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. Jing Liu, Xijun Liang, Danxia Zhou, Ling Lai, Tingting Fu, Yan Kong, Qian Zhou, Rick B. Vega, Min-Sheng Zhu, Daniel P. Kelly, Xiang Gao, and Zhenji Gan. Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative type fibers. However, the mechanism for coupling of mitochondrial function to muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499 parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1a-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, a known AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1a. Inhibition of Fnip1 reactivated AMPK/PGC-1a signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function. Keywords: muscle, contractile fiber type, mitochondrial function, microRNA, gene regulation RNA from three wild-type (non-transgenic (NTG)) and three miR-499 overexpressing (MCK-miR-499) mice was analyzed. three replicates of each are provided.
2016-09-03 | E-GEOD-72581 | biostudies-arrayexpress
Project description:The physical connection between mitochondria and endoplasmic or sarcoplasmic reticulum is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER/SR-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. The aim of this study was to describe the molecular and physiological functions of BCL2L13. Using a zebrafish knockout model, we assessed the physiological changes, alterations of skeletal muscle structure, differences in the muscle proteome, and mitochondrial metabolism caused by the loss of Bcl2l13. We used cellular models to define the subcellular location and the mechanistic role of Bcl2l13. The loss of Bcl2l13 in zebrafish decreased swimming capacity and activity. Skeletal muscle fast fiber cross sectional area was reduced in knockout fish. Muscle proteome uncovered changes in protein turnover, transmembrane transport and expression of Ca2+ signaling proteins compared to wild type fish.
2024-07-25 | PXD044765 | Pride
Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)
2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress
Project description:In mammals, loss of food intake and reduced mechanical loading/activity of skeletal muscles leads to a very rapid loss in mass and function. However, during hibernation in bears, despite spending months without feeding and with very modest muscle activity, only moderate muscle wasting is observed. Part of this tissue sparing is due to a highly reduced metabolic activity in almost all tissues, including skeletal muscle. Interestingly, myosin, one of the most abundant proteins in skeletal muscle, can have different metabolic activities in inactive muscle. Therefore, to evaluate the functional and metabolic alterations in hibernating muscles, we performed an analysis on a single muscle fiber level. Individual fibers were taken from biopsies of the same bears either during hibernation or during the active phase in the summer. We confirm that muscle fibers from hibernating bears show no loss of fiber size and a mild reduction in force generating capacity. However, ATPase activity of single muscle fibers taken from hibernating bears show a significant reduction in ATPase activity, which is due to a reduced ATP turnover by myosin. By performing a single fiber proteomics analysis, we could determine in a fiber type specific manner that muscle fibers undergo a major remodeling of their proteome. Both type 2A and type 1/2A mixed fibers show a marked reduction in mitochondrial proteins during hibernation, with a decrease in proteins linked to the TCA cycle and mitochondrial translation.
2024-12-06 | PXD050980 | Pride
Project description:Skeletal muscle insulin resistance, an early metabolic defect in the pathogenesis of type 2 diabetes, may be a cause or consequence of altered protein expressions profiles. Proteomics technology offers enormous promise to investigate molecular mechanisms underlying pathologies, however, the analysis of skeletal muscle is challenging. Using a state-of-the-art mass spectrometry (MS) based workflow, we performed a global proteomics analysis of skeletal muscle from leptin-deficient, obese, type 2 diabetic (ob/ob) and lean mice, identifying more than 6,000 proteins with 118 proteins differentially regulated in obesity. This included protein kinases, phosphatases, and secreted and fiber type associated proteins. Enzymes involved in lipid metabolism in skeletal muscle from ob/ob mice were increased, providing evidence against reduced fatty acid oxidation in lipid-induced insulin resistance. Mitochondrial and peroxisomal proteins, as well as components of pyruvate and lactate metabolism were likewise increased. Finally, the skeletal muscle proteome from ob/ob mice displayed a shift towards the ‘slow fiber type’. This detailed characterization of obese rodent models of type 2 diabetes demonstrates an efficient workflow for skeletal muscle proteomics, which may easily be adapted to other complex tissues.
2018-01-26 | PXD007697 | Pride