Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy

Majumder, Avisek; Behera, Jyotirmaya; Jeremić, Nevena; Tyagi, Suresh C.

doi:10.1002/jcb.25841

Cited by 29 publications

(35 citation statements)

References 104 publications

(190 reference statements)

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“…There are also several other drivers like age, sex, physical activity, alcohol intake, certain medications, and different disease conditions (such as type 2-diabetes) that can also modulate the functioning Met cycle leading to an increased total Hcy concentration in the blood (Diakoumopoulou et al 2005). Hyperhomocysteinemia (HHcy) has been associated with severe skeletal muscle dysfunction (Brustolin et al 2010;Kanwar et al 1976;Kolling et al 2013;Majumder et al 2017;Miller et al 2000;Valentino et al 2010;Veeranki et al 2015;Voskoboeva et al 2018;Zoccolella et al 2008), but the precise mechanism(s) is still unknown. Previous studies found that HHcy causes endothelial cell (EC) injury (Wang et al 1997), inhibition of EC proliferation (Zou et al 2011), reduction of bioavailability of vasoregulatory mediators (nitric oxide and endothelin) (Upchurch et al 1997), and induction of oxidative/ER-stress Tyagi et al 2005;Werstuck et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

et al. 2018

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Neoangiogenesis is a fundamental process which helps to meet energy requirements, tissue growth, and wound healing. Although previous studies showed that Peroxisome proliferator‐activated receptor (PPAR‐γ) regulates neoangiogenesis via upregulation of vascular endothelial growth factor (VEGF), and both VEGF and PPAR‐γ expressions were inhibited during hyperhomocysteinemic (HHcy), whether these two processes could trigger pathological effects in skeletal muscle via compromising neoangiogenesis has not been studied yet. Unfortunately, there are no treatment options available to date for ameliorating HHcy‐mediated neoangiogenic defects. Hydrogen sulfide (H2S) is a novel gasotransmitter that can induce PPAR‐γ levels. However, patients with cystathionine‐β‐synthase (CBS) mutation(s) cannot produce a sufficient amount of H2S. We hypothesized that exogenous supplementation of H2S might improve HHcy‐mediated poor neoangiogenesis via the PPAR‐γ/VEGF axis. To examine this, we created a hind limb femoral artery ligation (FAL) in CBS +/− mouse model and treated them with GYY4137 (a long‐acting H2S donor compound) for 21 days. To evaluate neoangiogenesis, we used barium sulfate angiography and laser Doppler blood flow measurements in the ischemic hind limbs of experimental mice post‐FAL to assess blood flow. Proteins and mRNAs levels were studied by Western blots and qPCR analyses. HIF1‐α, VEGF, PPAR‐γ and p‐eNOS expressions were attenuated in skeletal muscle of CBS +/− mice after 21 days of FAL in comparison to wild‐type (WT) mice, that were improved via GYY4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐FAL CBS +/− mice compared to WT mice and these effects were ameliorated by GYY4137. Moreover, we found that plasma nitrite levels were decreased in post‐FAL CBS +/− mice compared to WT mice, which were mitigated by GYY4137 supplementation. These results suggest that HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing PPAR‐γ/VEGF axis and that GYY4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of HHcy conditions.

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Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

et al. 2018

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“…In our study we present for the first time changes of the synaptic transmission during postnatal development in rat neuromuscular junction caused by elevated levels of the endogenous amino acid HCY during the prenatal period. Several previous studies reported that an increased level of HCY leads to functional impairments and weakness of skeletal muscle (Veeranki and Tyagi, 2013; Ng et al, 2012; Swart et al, 2013; Majumder et al, 2017, 2018a,b). Children born with severe homocystinuria due to CBS deficiency exhibit low body weight and skeletal muscle myopathy (Picker and Levy, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, using a spectrophotometric assay we found an increase of H 2 O 2 level and lipid peroxidation in muscles of neonatal and adult rats in the hHCY group. Apparently, this increased level of ROS can cause oxidation of various functionally important proteins, including the presynaptic transmitter releasing machinery which is the most redox‐sensitive part of the motor synapse (Giniatullin et al, 2006; Majumder et al, 2017; Veeranki and Tyagi, 2013) and as a result causes the functional changes of neuromuscular synapses in hHCY.…”

Section: Discussionmentioning

confidence: 99%

“…hHCY is often followed by skeletal muscle dysfunctions, evidenced by muscle weakness, less fatigue resistance due to oxidative stress, inflammation and endoplasmic reticulum stress in mice (Swart et al, 2013; Schweinberger et al, 2014; Veeranki and Tyagi, 2015; Majumder et al, 2017, 2018a,b). The elevated levels of HCY are associated with neurodegenerative disorders and amyotrophic lateral sclerosis (ALS) (McCully, 2017; Sharma et al, 2015; Swart et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…25-50 μM of HCY corresponds to moderate hHCY and higher concentrations (> 100 μM) are considered as severe form of hHCY in case of inborn failures of homocysteine metabolism (Jacobsen, 1998;Sharma et al, 2015). hHCY is often followed by skeletal muscle dysfunctions, evidenced by muscle weakness, less fatigue resistance due to oxidative stress, inflammation and endoplasmic reticulum stress in mice (Swart et al, T 2013;Schweinberger et al, 2014;Majumder et al, 2017Majumder et al, , 2018a. The elevated levels of HCY are associated with neurodegenerative disorders and amyotrophic lateral sclerosis (ALS) (McCully, 2017;Sharma et al, 2015;Swart et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Prenatal hyperhomocysteinemia induces oxidative stress and accelerates ‘aging’ of mammalian neuromuscular synapses

Khuzakhmetova

Yakovleva

Dmitrieva

et al. 2019

Intl J of Devlp Neuroscience

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Enhanced levels of homocysteine during pregnancy induce oxidative stress and contribute to many age‐related diseases. In this study, we analyzed age‐dependent synaptic modifications in developing neuromuscular synapses of rats with prenatal hyperhomocysteinemia (hHCY). One of the main findings indicate that the intensity and the timing of transmitter release in synapses of neonatal (P6 and P10) hHCY rats acquired features of matured synaptic transmission of adult rats. The amplitude and frequency of miniature end‐plate currents (MEPCs) and evoked transmitter release were higher in neonatal hHCY animals compared to the control group. Analysis of the kinetics of neurotransmitter release demonstrated more synchronized release in neonatal rats with hHCY. At the same time lower release probability was observed in adults with hHCY. Spontaneous transmitter release in neonates with hHCY was inhibited by hydrogen peroxide (H2O2) whereas in controls this oxidant was effective only in adult animals indicating a higher susceptibility of motor nerve terminals to oxidative stress. The morphology and the intensity of endocytosis of synaptic vesicles in motor nerve endings was assessed using the fluorescence dye FM 1‐43. Adult‐like synapses were found in neonates with hHCY which were characterized by a larger area of presynaptic terminals compared to controls. No difference in the intensity of FM 1‐43 fluorescence was observed between two groups of animals. Prenatal hHCY resulted in reduced muscle strength assessed by the Paw Grip Endurance test. Using biochemical assays we found an increased level of H2O2 and lipid peroxidation products in the diaphragm muscles of hHCY rats. This was associated with a lowered activity of superoxide dismutase and glutathione peroxidase. Our data indicate that prenatal hHCY induces oxidative stress and apparent faster functional and morphological “maturation” of motor synapses. Our results uncover synaptic mechanisms of disrupted muscle function observed in hHCY conditions which may contribute to the pathogenesis of motor neuronal diseases associated with enhanced level of homocysteine.

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Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective

Majumder

Singh

George

et al. 2018

J of Cellular Biochemistry

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Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body’s vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy’s effects on the vascular system. An ancient Indian form of exercise called ‘yoga’ causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia‐reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti‐pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti‐inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow–derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior’s role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

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Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy

Cited by 29 publications

References 104 publications

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

Prenatal hyperhomocysteinemia induces oxidative stress and accelerates ‘aging’ of mammalian neuromuscular synapses

Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective

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