scholarly journals Mitochondrial dysregulation and muscle disuse atrophy

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1621 ◽  
Author(s):  
Li Li Ji ◽  
Dongwook Yeo
Keyword(s):  
Muscle Atrophy ◽  
Contractile Activity ◽  
Critical Role ◽  
Physiological Adaptation ◽  
Ros Generation ◽  
Disuse Atrophy ◽  
Cellular Functions ◽  
Mitochondrial Homeostasis ◽  
Muscle Disuse

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 in vivo DNA transfection can restore mitochondrial homeostasis and reverse myocyte atrophy supports the “mitostasis theory of muscle atrophy”.

scholarly journals Hindlimb Immobilization Increases IL-1β and Cdkn2a Expression in Skeletal Muscle Fibro-Adipogenic Progenitor Cells: A Link Between Senescence and Muscle Disuse Atrophy

2022 ◽  
Vol 9 ◽  
Author(s):  
Emily Parker ◽  
Andrew Khayrullin ◽  
Andrew Kent ◽  
Bharati Mendhe ◽  
Khairat Bahgat Youssef El Baradie ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Stem Cell Population ◽  
Disuse Atrophy ◽  
Rna Seq ◽  
Muscle Disuse ◽  
Increased Risk

Loss of muscle mass and strength contributes to decreased independence and an increased risk for morbidity and mortality. A better understanding of the cellular and molecular mechanisms underlying muscle atrophy therefore has significant clinical and therapeutic implications. Fibro-adipogenic progenitors (FAPs) are a skeletal muscle resident stem cell population that have recently been shown to play vital roles in muscle regeneration and muscle hypertrophy; however, the role that these cells play in muscle disuse atrophy is not well understood. We investigated the role of FAPs in disuse atrophy in vivo utilizing a 2-week single hindlimb immobilization model. RNA-seq was performed on FAPs isolated from the immobilized and non-immobilized limb. The RNAseq data show that IL-1β is significantly upregulated in FAPs following 2 weeks of immobilization, which we confirmed using droplet-digital PCR (ddPCR). We further validated the RNA-seq and ddPCR data from muscle in situ using RNAscope technology. IL-1β is recognized as a key component of the senescence-associated secretory phenotype, or SASP. We then tested the hypothesis that FAPs from the immobilized limb would show elevated senescence measured by cyclin-dependent kinase inhibitor 2A (Cdkn2a) expression as a senescence marker. The ddPCR and RNAscope data both revealed increased Cdkn2a expression in FAPs with immobilization. These data suggest that the gene expression profile of FAPs is significantly altered with disuse, and that disuse itself may drive senescence in FAPs further contributing to muscle atrophy.

scholarly journals A critical role for Apc in hematopoietic stem and progenitor cell survival

2008 ◽  
Vol 205 (9) ◽  
pp. 2163-2175 ◽  
Author(s):  
Zhijian Qian ◽  
Lina Chen ◽  
Anthony A. Fernald ◽  
Bart O. Williams ◽  
Michelle M. Le Beau
Keyword(s):  
Chromosome Segregation ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Cellular Functions ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Cell Cycle Entry ◽  
Genes Encoding

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.

scholarly journals Chemokine-biased robust self-organizing polarization of migrating cells in vivo

2019 ◽  
Author(s):  
Adan Olguin-Olguin ◽  
Anne Aalto ◽  
Benoît Maugis ◽  
Michal Reichman-Fried ◽  
Erez Raz
Keyword(s):  
Primordial Germ Cells ◽  
Critical Role ◽  
Cell Polarization ◽  
Cellular Functions ◽  
Motile Cells ◽  
Cell Front ◽  
Specific Proteins ◽  
Migrating Cells

The mechanisms facilitating the establishment of front-rear polarity in migrating cells are not fully understood, in particular in the context of bleb-driven directional migration. To gain further insight into this issue we utilized the migration of zebrafish primordial germ cells (PGCs) as an in vivo model. We followed the molecular and morphological cascade that converts apolar cells into polarized bleb-forming motile cells and analyzed the cross dependency among the different cellular functions we identified. Our results underline the critical role of antagonistic interactions between the front and the rear, in particular the role of biophysical processes including formation of barriers and transport of specific proteins to the back of the cell. These interactions direct the formation of blebs to a specific part of the cell that is specified as the cell front. In this way, spontaneous cell polarization facilitates non-directional cell motility and when biased by chemokine signals leads to migration towards specific locations.

scholarly journals ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chuangyu Wen ◽  
Huihui Wang ◽  
Xiaobin Wu ◽  
Lu He ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Critical Role ◽  
Thioredoxin Reductase ◽  
Akt Pathway ◽  
Ros Generation ◽  
In Vivo Models ◽  
M Phase ◽  
Tumorigenesis And Progression ◽  
Induced Apoptosis

Abstract Novel drugs are urgently needed for gastric cancer (GC) treatment. The thioredoxin-thioredoxin reductase (TRX-TRXR) system has been found to play a critical role in GC tumorigenesis and progression. Thus, agents that target the TRX-TRXR system may be highly efficacious as GC treatments. In this study, we showed that chaetocin, a natural product isolated from the Chaetomium species of fungi, inhibited proliferation, induced G2/M phase arrest and caspase-dependent apoptosis in both in vitro and in vivo models (cell xenografts and patient-derived xenografts) of GC. Chaetocin inactivated TRXR-1, resulting in the accumulation of reactive oxygen species (ROS) in GC cells; overexpression of TRX-1 as well as cotreatment of GC cells with the ROS scavenger N-acetyl-L-cysteine attenuated chaetocin-induced apoptosis; chaetocin-induced apoptosis was significantly increased when GC cells were cotreated with auranofin. Moreover, chaetocin was shown to inactivate the PI3K/AKT pathway by inducing ROS generation; AKT-1 overexpression also attenuated chaetocin-induced apoptosis. Taken together, these results reveal that chaetocin induces the excessive accumulation of ROS via inhibition of TRXR-1. This is followed by PI3K/AKT pathway inactivation, which ultimately inhibits proliferation and induces caspase-dependent apoptosis in GC cells. Chaetocin therefore may be a potential agent for GC treatment.

scholarly journals The Microtubule Severing Protein Katanin Regulates Proliferation of Neuronal Progenitors in Embryonic and Adult Neurogenesis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Franco L. Lombino ◽  
Mary Muhia ◽  
Jeffrey Lopez-Rojas ◽  
Monika S. Brill ◽  
Edda Thies ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Critical Role ◽  
Mammalian Brain ◽  
Cellular Functions ◽  
Microtubule Severing ◽  
Neuronal Progenitor ◽  
Neuronal Progenitors ◽  
Adult Hippocampus

Abstract Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.

scholarly journals Expression of a myosin regulatory light chain phosphorylation site mutant complements the cytokinesis and developmental defects of Dictyostelium RMLC null cells.

1994 ◽  
Vol 127 (6) ◽  
pp. 1945-1955 ◽  
Author(s):  
B D Ostrow ◽  
P Chen ◽  
R L Chisholm
Keyword(s):  
Atpase Activity ◽  
Light Chain ◽  
Contractile Activity ◽  
Phosphorylation Site ◽  
Regulatory Light Chain ◽  
Site Directed Mutagenesis ◽  
Cellular Functions ◽  
Developmental Defects

In a number of systems phosphorylation of the regulatory light chain (RMLC) of myosin regulates the activity of myosin. In smooth muscle and vertebrate nonmuscle systems RMLC phosphorylation is required for contractile activity. In Dictyostelium discoideum phosphorylation of the RMLC regulates both ATPase activity and motor function. We have determined the site of phosphorylation on the Dictyostelium RMLC and used site-directed mutagenesis to replace the phosphorylated serine with an alanine. The mutant light chain was then expressed in RMLC null Dictyostelium cells (mLCR-) from an actin promoter on an integrating vector. The mutant RMLC was expressed at high levels and associated with the myosin heavy chain. RMLC bearing a ser13ala substitution was not phosphorylated in vitro by purified myosin light chain kinase, nor could phosphate be detected on the mutant RMLC in vivo. The mutant myosin had reduced actin-activated ATPase activity, comparable to fully dephosphorylated myosin. Unexpectedly, expression of the mutant RMLC rescued the primary phenotypic defects of the mlcR- cells to the same extent as did expression of wild-type RMLC. These results suggest that while phosphorylation of the Dictyostelium RMLC appears to be tightly regulated in vivo, it is not essential for myosin-dependent cellular functions.

scholarly journals Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning

2013 ◽  
Vol 304 (9) ◽  
pp. H1192-H1200 ◽  
Author(s):  
Cevher Ozcan ◽  
Monica Palmeri ◽  
Tamas L. Horvath ◽  
Kerry S. Russell ◽  
Raymond R. Russell
Keyword(s):  
Protective Efficacy ◽  
Uncoupling Protein ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Left Ventricular ◽  
Ros Generation ◽  
In Vivo Models ◽  
Myocardial Energetics

Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3−/−) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3−/− mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3−/− mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3−/− mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3−/− hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3−/− hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3−/− mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R.

scholarly journals Phospholemman is not required for the acute stimulation of Na+-K+-ATPase α2-activity during skeletal muscle fatigue

2015 ◽  
Vol 309 (12) ◽  
pp. C813-C822 ◽  
Author(s):  
Palanikumar Manoharan ◽  
Tatiana L. Radzyukevich ◽  
Hesamedin Hakim Javadi ◽  
Cory A. Stiner ◽  
Julio A. Landero Figueroa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Capacity ◽  
Skeletal Muscles ◽  
Contractile Activity ◽  
Critical Role ◽  
Regulatory Subunit ◽  
Dependent Manner ◽  
Evoked Contractions ◽  
Stimulation Of

The Na+-K+-ATPase α2-isoform in skeletal muscle is rapidly stimulated during muscle use and plays a critical role in fatigue resistance. The acute mechanisms that stimulate α2-activity are not completely known. This study examines whether phosphorylation of phospholemman (PLM/FXYD1), a regulatory subunit of Na+-K+-ATPase, plays a role in the acute stimulation of α2 in working muscles. Mice lacking PLM (PLM KO) have a normal content of the α2-subunit and show normal exercise capacity, in contrast to the greatly reduced exercise capacity of mice that lack α2 in the skeletal muscles. Nerve-evoked contractions in vivo did not induce a change in total PLM or PLM phosphorylated at Ser63 or Ser68, in either WT or PLM KO. Isolated muscles of PLM KO mice maintain contraction and resist fatigue as well as wild type (WT). Rb+ transport by the α2-Na+-K+-ATPase is stimulated to the same extent in contracting WT and contracting PLM KO muscles. Phosphorylation of sarcolemmal membranes prepared from WT but not PLM KO skeletal muscles stimulates the activity of both α1 and α2 in a PLM-dependent manner. The stimulation occurs by an increase in Na+ affinity without significant change in Vmax and is more effective for α1 than α2. These results demonstrate that phosphorylation of PLM is capable of stimulating the activity of both isozymes in skeletal muscle; however, contractile activity alone is not sufficient to induce PLM phosphorylation. Importantly, acute stimulation of α2, sufficient to support exercise and oppose fatigue, does not require PLM or its phosphorylation.

scholarly journals Redox Signaling and Sarcopenia: Searching for the Primary Suspect

2021 ◽  
Vol 22 (16) ◽  
pp. 9045
Author(s):  
Nicholas A. Foreman ◽  
Anton S. Hesse ◽  
Li Li Ji
Keyword(s):  
Health Hazard ◽  
Critical Role ◽  
The Elderly ◽  
Redox Signaling ◽  
Ros Generation ◽  
Mitochondrial Homeostasis ◽  
Metabolic Functions ◽  
Age Related ◽  
And Function ◽  
Fundamental Mechanism

Sarcopenia, the age-related decline in muscle mass and function, derives from multiple etiological mechanisms. Accumulative research suggests that reactive oxygen species (ROS) generation plays a critical role in the development of this pathophysiological disorder. In this communication, we review the various signaling pathways that control muscle metabolic and functional integrity such as protein turnover, cell death and regeneration, inflammation, organismic damage, and metabolic functions. Although no single pathway can be identified as the most crucial factor that causes sarcopenia, age-associated dysregulation of redox signaling appears to underlie many deteriorations at physiological, subcellular, and molecular levels. Furthermore, discord of mitochondrial homeostasis with aging affects most observed problems and requires our attention. The search for the primary suspect of the fundamental mechanism for sarcopenia will likely take more intense research for the secret of this health hazard to the elderly to be unlocked.

scholarly journals LARP1 is a major phosphorylation substrate of mTORC1

2018 ◽  
Author(s):  
Bruno D. Fonseca ◽  
Jian-Jun Jia ◽  
Anne K. Hollensen ◽  
Roberta Pointet ◽  
Huy-Dung Hoang ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Cellular Functions ◽  
Multiple Substrates ◽  
Eif4f Complex ◽  
Mtorc1 Pathway ◽  
Terminal Oligopyrimidine

AbstractThe mammalian target of rapamycin complex 1 (mTORC1) controls critical cellular functions such as protein synthesis, lipid metabolism, protein turnover and ribosome biogenesis through the phosphorylation of multiple substrates. In this study, we examined the phosphorylation of a recently identified target of mTORC1: La-related protein 1 (LARP1), a member of the LARP superfamily. Previously, we and others have shown that LARP1 plays an important role in repressing TOP mRNA translation downstream of mTORC1. LARP1 binds the 7-methylguanosine triphosphate (m7Gppp) cap moiety and the adjacent 5’terminal oligopyrimidine (5’TOP) motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 plays a critical role in the control of TOP mRNA translation via LARP1 but the precise mechanism by which this occurs is incompletely understood. The data described herein help to elucidate this process. Specifically, it show that: (i) mTORC1 interacts with LARP1, but not other LARP superfamily members, via the C-terminal region that comprises the DM15 domain, (ii) mTORC1 pathway controls the phosphorylation of multiple (up to 26) serine and threonine residues on LARP1 in vivo, (iii) mTORC1 regulates the binding of LARP1 to TOP mRNAs and (iv) phosphorylation of S689 by mTORC1 is particularly important for the association of the DM15 domain of LARP1 with the 5’UTR of RPS6 TOP mRNA. These data reveal LARP1 as a major substrate of mTORC1.

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