Abstract:
BACKGROUND:Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. METHODS:We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. RESULTS:H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability. CONCLUSIONS:These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.
journal_name
Skelet Musclejournal_title
Skeletal muscleauthors
Doig CL,Zielinska AE,Fletcher RS,Oakey LA,Elhassan YS,Garten A,Cartwright D,Heising S,Alsheri A,Watson DG,Prehn C,Adamski J,Tennant DA,Lavery GGdoi
10.1186/s13395-019-0216-zsubject
Has Abstractpub_date
2020-02-19 00:00:00pages
5issue
1issn
2044-5040pii
10.1186/s13395-019-0216-zjournal_volume
10pub_type
杂志文章相关文献
Skeletal Muscle文献大全abstract:BACKGROUND:A hallmark of muscular dystrophies is the replacement of muscle by connective tissue. Muscle biopsies from patients severely affected with facioscapulohumeral muscular dystrophy (FSHD) may contain few myogenic cells. Because the chromosomal contraction at 4q35 linked to FSHD is thought to cause a defect with...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/2044-5040-1-12
更新日期:2011-03-08 00:00:00
abstract:BACKGROUND:Although excitation-contraction (EC) coupling in skeletal muscle relies on physical activation of the skeletal ryanodine receptor (RyR1) Ca(2+) release channel by dihydropyridine receptors (DHPRs), the activation pathway between the DHPR and RyR1 remains unknown. However, the pathway includes the DHPR β1a su...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-015-0049-3
更新日期:2015-07-22 00:00:00
abstract:BACKGROUND:Critical illness myopathy (CIM) is associated with severe skeletal muscle wasting and impaired function in intensive care unit (ICU) patients. The mechanisms underlying CIM remain incompletely understood. To elucidate the biological activities occurring at the transcriptional level in the skeletal muscle of ...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-019-0194-1
更新日期:2019-04-16 00:00:00
abstract::Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathway...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/2044-5040-1-2
更新日期:2011-01-24 00:00:00
abstract:BACKGROUND:A low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD). Oxidative damage and mitochondrial dysfunction associated with the upregulation of p66SHC and FoxO3a have been shown to contribute to muscle atrophy. This study aimed to d...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-018-0164-z
更新日期:2018-05-31 00:00:00
abstract:BACKGROUND:The spatial organization of eukaryotic genomes facilitates and reflects the underlying nuclear processes that are occurring in the cell. As such, the spatial organization of a genome represents a window on the genome biology that enables analysis of the nuclear regulatory processes that contribute to mammali...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-017-0122-1
更新日期:2017-04-05 00:00:00
abstract:BACKGROUND:hTERT/cdk4 immortalized myogenic human cell lines represent an important tool for skeletal muscle research, being used as therapeutically pertinent models of various neuromuscular disorders and in numerous fundamental studies of muscle cell function. However, the cell cycle is linked to other cellular proces...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-016-0115-5
更新日期:2016-12-08 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to...
journal_title:Skeletal muscle
pub_type: 杂志文章,评审
doi:10.1186/s13395-017-0124-z
更新日期:2017-05-19 00:00:00
abstract:BACKGROUND:Muscle hypertrophy in the mdx mouse model of Duchenne muscular dystrophy (DMD) can partially compensate for the loss of dystrophin by maintaining peak force production. Histopathology examination of the hypertrophic muscles suggests the hypertrophy primarily results from the addition of myofibers, and is acc...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/2044-5040-4-10
更新日期:2014-05-23 00:00:00
abstract:BACKGROUND:Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; however, the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Although exogenous protein treatment and overexpression studies indicated IL-15...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-015-0058-2
更新日期:2015-09-28 00:00:00
abstract:BACKGROUND:Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-016-0077-7
更新日期:2016-01-21 00:00:00
abstract:BACKGROUND:Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb g...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-018-0163-0
更新日期:2018-05-31 00:00:00
abstract:BACKGROUND:Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by mutations in the dystrophin gene. Loss of dystrophin prevents the formation of a critical connection between the muscle cell membrane and the extracellular matrix. Overexpression of sarcospan (SSPN) in the mouse model of DMD restore...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-020-00244-3
更新日期:2020-09-18 00:00:00
abstract:BACKGROUND:Motor neurons control muscle contraction by initiating action potentials in muscle. Denervation of muscle from motor neurons leads to muscle atrophy, which is linked to mitochondrial dysfunction. It is known that denervation promotes mitochondrial reactive oxygen species (ROS) production in muscle, whereas t...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-017-0123-0
更新日期:2017-04-10 00:00:00
abstract:BACKGROUND:Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during pos...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-019-0191-4
更新日期:2019-02-21 00:00:00
abstract:BACKGROUND:shRNA lentiviral vectors are extensively used for gene knockdowns in mammalian cells, and non-target shRNAs typically are considered the proper experimental control for general changes caused by RNAi. However, the effects of non-target lentivirus controls on the modulation of cell signaling pathways remain l...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-017-0125-y
更新日期:2017-05-15 00:00:00
abstract:BACKGROUND:Large-scale expansion of myogenic progenitors is necessary to support the development of high-throughput cellular assays in vitro and to advance genetic engineering approaches necessary to develop cellular therapies for rare muscle diseases. However, optimization has not been performed in order to maintain t...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-016-0116-4
更新日期:2016-12-13 00:00:00
abstract:BACKGROUND:Ca(2+) influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca(2+) permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed. METHODS:We generated a mouse with a Ca(2+) binding and/o...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-014-0027-1
更新日期:2015-01-29 00:00:00
abstract:BACKGROUND:During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors an...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-019-0210-5
更新日期:2019-09-18 00:00:00
abstract:BACKGROUND:Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder stemming from a loss of functional dystrophin. Current therapeutic options for DMD are limited, as small molecule modalities remain largely unable to decrease the incidence or mitigate the consequences of repetitive mechanical insults...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-020-00249-y
更新日期:2020-10-22 00:00:00
abstract::Muscular dystrophies are a large heterogeneous group of inherited diseases that cause progressive muscle weakness and permanent muscle damage. Very few muscular dystrophies show sufficient specific clinical features to allow a definite diagnosis. Because of the currently limited capacity to screen for numerous genes s...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/2044-5040-1-24
更新日期:2011-06-24 00:00:00
abstract:BACKGROUND:Gene therapy strategies are promising therapeutic options for monogenic muscular dystrophies, with several currently underways. The adeno-associated viral (AAV) vector is among the most effective gene delivery systems. However, transduction efficiency in skeletal muscles varies between AAV serotypes, with th...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-015-0064-4
更新日期:2015-11-10 00:00:00
abstract:BACKGROUND:Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has rema...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-020-00254-1
更新日期:2020-12-11 00:00:00
abstract:BACKGROUND:Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initi...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-017-0148-4
更新日期:2018-01-12 00:00:00
abstract:BACKGROUND:α-Dystroglycan is the highly glycosylated component of the dystrophin-glycoprotein complex (DGC) that binds with high-affinity to extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains via a unique heteropolysaccharide [-GlcA-beta1,3-Xyl-alpha1,3-]n called matriglycan. Changes in expressi...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-019-0195-0
更新日期:2019-05-04 00:00:00
abstract::Almost every muscle contains muscle spindles. These delicate sensory receptors inform the central nervous system (CNS) about changes in the length of individual muscles and the speed of stretching. With this information, the CNS computes the position and movement of our extremities in space, which is a requirement for...
journal_title:Skeletal muscle
pub_type: 杂志文章,评审
doi:10.1186/s13395-020-00258-x
更新日期:2021-01-07 00:00:00
abstract::In response to muscle injury, muscle stem cells integrate environmental cues in the damaged tissue to mediate regeneration. These environmental cues are tightly regulated to ensure expansion of muscle stem cell population to repair the damaged myofibers while allowing repopulation of the stem cell niche. These changes...
journal_title:Skeletal muscle
pub_type: 杂志文章,评审
doi:10.1186/s13395-020-00259-w
更新日期:2021-01-11 00:00:00
abstract:BACKGROUND:Satellite cells are residential muscle stem cells that express a paired box protein, PAX7. RESULTS:Here, we report a knock-in mouse line expressing a PAX7-enhanced yellow fluorescent protein (YFP) fusion protein that enables visualization of PAX7 protein dynamics in living satellite cells through YFP fluore...
journal_title:Skeletal muscle
pub_type: 杂志文章
doi:10.1186/s13395-018-0174-x
更新日期:2018-08-24 00:00:00
abstract::Following the publication of this paper [1], it was brought to the authors' attention that one of the contributing authors was left off of the paper. The authors apologize for the unfortunate oversight. In this correction paper, they have included Dr. Paola Tonino in the author list section. ...
journal_title:Skeletal muscle
pub_type: 已发布勘误
doi:10.1186/s13395-020-00223-8
更新日期:2020-04-20 00:00:00
abstract::The circadian oscillations of muscle genes are controlled either directly by the intrinsic muscle clock or by extrinsic factors, such as feeding, hormonal signals, or neural influences, which are in turn regulated by the central pacemaker, the suprachiasmatic nucleus of the hypothalamus. A unique feature of circadian ...
journal_title:Skeletal muscle
pub_type: 杂志文章,评审
doi:10.1186/s13395-016-0107-5
更新日期:2016-10-13 00:00:00