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1.
iScience ; 24(12): 103434, 2021 Dec 17.
Article in English | MEDLINE | ID: mdl-34877494

ABSTRACT

Inflammatory responses are crucial for regeneration following peripheral nerve injury (PNI). PNI triggers inflammatory responses at the site of injury. The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) sense foreign and self-DNA and trigger type I interferon (IFN) immune responses. We demonstrate here that following PNI, the cGAS/STING pathway is upregulated in the sciatic nerve of naive rats and dysregulated in old rats. In a nerve crush mouse model where STING is knocked out, myelin content in sciatic nerve is increased resulting in accelerated functional axon recovery. STING KO mice have lower macrophage number in sciatic nerve and decreased microglia activation in spinal cord 1 week post injury. STING activation regulated processing of colony stimulating factor 1 receptor (CSF1R) and microglia survival in vitro. Taking together, these data highlight a previously unrecognized role of STING in the regulation of nerve regeneration.

2.
Stem Cells Dev ; 29(13): 811-822, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32295491

ABSTRACT

Avascular necrosis (AVN) is a severe complication of immunosuppressant therapy or chemotherapy. A beneficial AVN therapy with core decompression (CD) and intraosseous infusion of mesenchymal stromal cells (MSCs) has been described in adult patients, but there are only few data on MSC applications in pediatric and young adult patients (PYAP). Between 2006 and 2015, 14 AVN lesions of 10 PYAP (6 females) with a median age of 16.9 years (range 8.5-25.8 years) received CD and intraosseous application of autologous MSCs. Data of these patients were analyzed regarding efficacy, safety, and feasibility of this procedure as AVN therapy and compared with a control group of 13 AVN lesions of 11 PYAP (5 females) with a median age of 17.9 years (range 13.5-27.5 years) who received CD only. During the follow-up analysis [MSC group: median 3.1 (1.6-5.8) years after CD; CD group: median 2.0 (1.5-8.5) years after CD], relative lesion sizes (as assessed by magnetic resonance imaging) compared with the initial lesion volume, were significantly lower (P < 0.05) in the MSC group (volume reduction to a median of 18.5%) when compared with the CD group (58.0%). One lesion in the MSC group comprised a complete remission. Size progression was not observed in either group. Clinical improvement (pain, mobility) was not significantly different between the two groups. None of the patients experienced treatment-related adverse effects. CD and additional MSC application was regarded safe, effective, feasible, and superior in reducing the lesion size when compared with CD only. Prospective, randomized clinical trials are needed to further evaluate these findings.


Subject(s)
Femur Head Necrosis/therapy , Long Term Adverse Effects/epidemiology , Mesenchymal Stem Cell Transplantation/adverse effects , Adolescent , Adult , Cells, Cultured , Female , Femur/diagnostic imaging , Femur/pathology , Femur Head Necrosis/drug therapy , Humans , Male , Mesenchymal Stem Cell Transplantation/methods , Steroids/therapeutic use , Transplantation, Autologous
3.
Cell Rep ; 21(11): 3003-3011, 2017 Dec 12.
Article in English | MEDLINE | ID: mdl-29241530

ABSTRACT

ATP citrate lyase (ACL) plays a key role in regulating mitochondrial function, as well as glucose and lipid metabolism in skeletal muscle. We report here that ACL silencing impairs myoblast and satellite cell (SC) differentiation, and it is accompanied by a decrease in fast myosin heavy chain isoforms and MYOD. Conversely, overexpression of ACL enhances MYOD levels and promotes myogenesis. Myogenesis is dependent on transcriptional but also other mechanisms. We show that ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression. ACL overexpression in murine skeletal muscle leads to improved regeneration after cardiotoxin-mediated damage. Thus, our findings suggest a mechanism for regulating SC differentiation and enhancing regeneration, which might be exploited for devising therapeutic approaches for treating skeletal muscle disease.


Subject(s)
ATP Citrate (pro-S)-Lyase/genetics , Histones/genetics , Muscle, Skeletal/metabolism , MyoD Protein/genetics , Regeneration/genetics , Satellite Cells, Skeletal Muscle/metabolism , ATP Citrate (pro-S)-Lyase/metabolism , Acetylation , Animals , Cardiotoxins/toxicity , Cell Differentiation , Gene Expression Regulation , Histones/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Muscle Development/genetics , Muscle, Skeletal/cytology , Muscle, Skeletal/drug effects , MyoD Protein/metabolism , Primary Cell Culture , Satellite Cells, Skeletal Muscle/cytology , Satellite Cells, Skeletal Muscle/drug effects , Signal Transduction , Transcription, Genetic
4.
Cell Metab ; 21(6): 868-76, 2015 Jun 02.
Article in English | MEDLINE | ID: mdl-26039450

ABSTRACT

Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT-dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP.


Subject(s)
ATP Citrate (pro-S)-Lyase/metabolism , Citric Acid/metabolism , Mitochondria, Muscle/metabolism , Muscle Fibers, Skeletal/enzymology , Oxygen Consumption/physiology , Signal Transduction/physiology , Adenosine Triphosphate/metabolism , Cardiolipins/metabolism , Humans , Insulin-Like Growth Factor I/metabolism
5.
Sci Signal ; 4(201): ra80, 2011 Nov 29.
Article in English | MEDLINE | ID: mdl-22126963

ABSTRACT

Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.


Subject(s)
Cell Differentiation , GTP-Binding Protein alpha Subunits, G12-G13/metabolism , Myoblasts, Skeletal/enzymology , Regeneration , Signal Transduction , Animals , Enzyme Activation/genetics , GTP-Binding Protein alpha Subunits, G12-G13/genetics , HEK293 Cells , Humans , Hypertrophy/enzymology , Hypertrophy/genetics , Hypertrophy/pathology , Mice , Mice, Transgenic , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscular Atrophy/enzymology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Mutation , Myoblasts, Skeletal/pathology , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Protein Kinase C/genetics , Protein Kinase C/metabolism , Tripartite Motif Proteins , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
6.
Am J Physiol Heart Circ Physiol ; 291(6): H2714-22, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16766641

ABSTRACT

The objective of this study was to identify differentially expressed genes in the mechanically unloaded rat heart by suppression subtractive hybridization. In male Wistar-Kyoto rats, mechanical unloading was achieved by infrarenal heterotopic heart transplantation. Differentially expressed genes were investigated systematically by suppression subtractive hybridization. Selected targets were validated by Northern blot analysis, real-time RT-PCR, and immunoblot analysis. Maximal ADP-stimulated oxygen consumption (state 3) was measured in isolated mitochondria. Transplantation caused atrophy (heart-to-body weight ratio: 1.6 +/- 0.1 vs. 2.4 +/- 0.1, P < 0.001). We selected 1,880 clones from the subtractive hybridization procedure (940 forward and 940 reverse runs assessing up- or downregulation). The first screen verified 465 forward and 140 reverse clones, and the second screen verified 67 forward and 30 reverse clones. On sequencing of 24 forward and 23 reverse clones, 9 forward and 14 reverse homologies to known genes were found. Specifically, we identified reduced mRNA expression of complex I (-49%, P < 0.05) and complex II (-61%, P < 0.001) of the respiratory chain. Significant reductions were also observed on the respiratory chain protein level: -42% for complex I (P < 0.01), -57% for complex II (P < 0.05), and -65% for complex IV (P < 0.05). Consistent with changes in gene and protein expression, state 3 respiration was significantly decreased in isolated mitochondria of atrophied hearts, with glutamate and succinate as substrates: 85 +/- 27 vs. 224 +/- 32 natoms O.min(-1).mg(-1) with glutamate (P < 0.01) and 59 +/- 18 vs. 154 +/- 30 natoms O.min(-1).mg(-1) with succinate (P < 0.05). Subtractive hybridization indicates major changes in overall gene expression by mechanical unloading and specifically identified downregulation of respiratory chain genes. This observation is functionally relevant and provides a mechanism for the regulation of respiratory capacity in response to chronic mechanical unloading.


Subject(s)
Electron Transport/genetics , Gene Expression Regulation/physiology , Heart/physiopathology , Hybridization, Genetic , Suppression, Genetic , Animals , Atrophy/genetics , Atrophy/physiopathology , Biomechanical Phenomena , DNA/genetics , Down-Regulation/physiology , Electron Transport/physiology , Heart Transplantation/physiology , Male , Mitochondria, Heart/physiology , Myocardium/metabolism , Myocardium/pathology , RNA, Messenger/genetics , Rats , Rats, Inbred WKY , Transplantation, Heterotopic
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