Characterization of myofiber‐type‐specific molecules using mass spectrometry imaging

Goto‐Inoue, Naoko; Morisasa, Mizuki; Machida, Kazumasa; Furuichi, Yukio; Fujii, Nobuharu; Miura, Shinji; Mori, Tsukasa

doi:10.1002/rcm.8319

Cited by 16 publications

(15 citation statements)

References 21 publications

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“…In addition, we observed the specific localization of PCs by MS imaging, since each PC molecule is distributed differently through the muscle, as described in our study previously 29 . We found that AA-containing PC, one of the lipid molecules, is significantly modulated by muscle atrophy, showing specific localization in the deep region that consists of slow-twitch fibers Fig.…”

Section: Discussionmentioning

confidence: 54%

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

et al. 2021

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Muscle atrophy refers to skeletal muscle loss and dysfunction that affects glucose and lipid metabolism. Moreover, muscle atrophy is manifested in cancer, diabetes, and obesity. In this study, we focused on lipid metabolism during muscle atrophy. We observed that the gastrocnemius muscle was associated with significant atrophy with 8 days of immobilization of hind limb joints and that muscle atrophy occurred regardless of the muscle fiber type. Further, we performed lipid analyses using thin layer chromatography, liquid chromatography-mass spectrometry, and mass spectrometry imaging. Total amounts of triacylglycerol, phosphatidylserine, and sphingomyelin were found to be increased in the immobilized muscle. Additionally, we found that specific molecular species of phosphatidylserine, phosphatidylcholine, and sphingomyelin were increased by immobilization. Furthermore, the expression of adipose triglyceride lipase and the activity of cyclooxygenase-2 were significantly reduced by atrophy. From these results, it was revealed that lipid accumulation and metabolic changes in specific fatty acids occur during disuse muscle atrophy. The present study holds implications in validating preventive treatment strategies for muscle atrophy.

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Section: Discussionmentioning

confidence: 54%

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

et al. 2021

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“…Specifically, analysis of fibre types showed that Alkbh5 deficiency mainly inhibited type II fibres atrophy, but had no significant effect on type I fibres ( Figure S3). This may be because the main myofibre in the GAS muscle was Type II or fast‐twitch fibres 23 . Western blot and qPCR showed that Alkbh5 knockout significantly suppressed FoxO3, Atrogin1 and MuRF1 levels in denervated GAS muscles, compared with the control group ( Figure 3L–3N).…”

Section: Resultsmentioning

confidence: 94%

m⁶A demethylase ALKBH5 drives denervation‐induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling

Liu

Zhou

Wang

et al. 2022

J cachexia sarcopenia muscle

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Background Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the treatment of primary neuropathies, it is a clinical condition that should be investigated. FoxO3 activation is an indispensable mechanism in denervation-induced muscle atrophy; however, upstream factors that control FoxO3 expression and activity have not been fully elucidated. N 6 -methyladenosine (m 6 A) methylation is a novel mode of epitranscriptional gene regulation that affects several cellular processes. However, the biological significance of m 6 A modification in FoxO3-dependent atrophy is unknown. Methods We performed gain-of-function and loss-of-function experiments and used denervation-induced muscle atrophy mouse model to evaluate the effects of m 6 A modification on muscle mass control and FoxO3 activation. m 6 A-sequencing and mass spectrometry analyses were used to establish whether histone deacetylase 4 (HDAC4) is a mediator of m 6 A demethylase ALKBH5 regulation of FoxO3. A series of cellular and molecular biological experiments (western blot, immunoprecipitation, half-life assay, m 6 A-MeRIP-qPCR, and luciferase reporter assays among others) were performed to investigate regulatory relationships among ALKBH5, HDAC4, and FoxO3. Results In skeletal muscles, denervation was associated with a 20.7-31.9% decrease in m 6 A levels (P < 0.01) and a 35.6-115.2% increase in demethylase ALKBH5 protein levels (P < 0.05). Overexpressed ALKBH5 reduced m 6 A levels, activated FoxO3 signalling, and induced excess loss in muscle wet weight (À10.3% for innervation and À11.4% for denervation, P < 0.05) as well as a decrease in myofibre cross-sectional areas (À35.8% for innervation and À33.3% for denervation, P < 0.05) during innervation and denervation. Specific deletion of Alkbh5 in the skeletal muscles prevented FoxO3 activation and protected mice from denervation-induced muscle atrophy, as evidenced by increased muscle mass (+16.0%, P < 0.05), size (+50.0%, P < 0.05) and MyHC expression (+32.6%, P < 0.05). Mechanistically, HDAC4 was established to be a crucial central mediator for ALKBH5 in enhancing FoxO3 signalling in denervated muscles. ALKBH5 demethylates and stabilizes Hdac4 mRNA. HDAC4 interacts with and deacetylates FoxO3, resulting in a significant increase in FoxO3 expression (+61.3-82.5%, P < 0.01) and activity (+51.6-122.0%, P < 0.001). Conclusions Our findings elucidate on the roles and mechanisms of ALKBH5-mediated m 6 A demethylation in the control of muscle mass during denervation and activation of FoxO3 signalling by targeting HDAC4. These results suggest that ALKBH5 is a potential therapeutic target for neurogenic muscle atrophy.

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“…Our study showed that intact myofibers were highly enriched in lipids, of which, various lipids were specifically enriched in MyHC‐2A‐negative myofibers. Different forms of PC lipids detected with MALDI‐MSI were reported to be MyHC‐isoform specific 15,41 . The limitation of the MALDI‐MSI the ability to identify the exact lipid conformation 42 .…”

Section: Discussionmentioning

confidence: 99%

The metabolic landscape in chronic rotator cuff tear reveals tissue‐region‐specific signatures

Olie

Zeijl

Abdellaoui

et al. 2021

J cachexia sarcopenia muscle

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Background Degeneration of shoulder muscle tissues often result in tearing, causing pain, disability and loss of independence. Differential muscle involvement patterns have been reported in tears of shoulder muscles, yet the molecules involved in this pathology are poorly understood. The spatial distribution of biomolecules across the affected tissue can be accurately obtained with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The goal of this pilot study was to decipher the metabolic landscape across shoulder muscle tissues and to identify signatures of degenerated muscles in chronic conditions. Methods Paired biopsies of two rotator cuff muscles, torn infraspinatus and intact teres minor, together with an intact shoulder muscle, the deltoid, were collected during an open tendon transfer surgery. Five patients, average age 65.2 ± 3.8 years, were selected for spatial metabolic profiling using high-spatial resolution (MALDI-TOF) and high-mass resolution (MALDI-FTICR) MSI in negative or positive ion mode. Metabolic signatures were identified using data-driven analysis. Verifications of spatial localization for selected metabolic signatures were carried out using antibody immunohistology. Results Data-driven analysis revealed major metabolic differences between intact and degenerated regions across all muscles. The area of degenerated regions, encompassed of fat, inflammation and fibrosis, significantly increased in both rotator cuff muscles, teres minor (27.9%) and infraspinatus (22.8%), compared with the deltoid (8.7%). The intact regions were characterized by 49 features, among which lipids were recognized. Several of the identified lipids were specifically enriched in certain myofiber types. Degenerated regions were specifically marked by the presence of 37 features. Heme was the most abundant metabolite in degenerated regions, whereas Heme oxygenase-1 (HO-1), which catabolizes heme, was found in intact regions. Higher HO-1 levels correlated with lower heme accumulation. Conclusions Degenerated regions are distinguished from intact regions by their metabolome profile. A muscle-specific metabolome profile was not identified. The area of tissue degeneration significantly differs between the three examined muscles. Higher HO-1 levels in intact regions concurred with lower heme levels in degenerated regions. Moreover, HO-1 levels discriminated between dysfunctional and functional rotator cuff muscles. Additionally, the enrichment of specific lipids in certain myofiber types suggests that lipid metabolism differs between myofiber types. The signature metabolites can open options to develop personalized treatments for chronic shoulder muscles degeneration.

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Characterization of myofiber‐type‐specific molecules using mass spectrometry imaging

Cited by 16 publications

References 21 publications

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

m⁶A demethylase ALKBH5 drives denervation‐induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling

The metabolic landscape in chronic rotator cuff tear reveals tissue‐region‐specific signatures

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Characterization of myofiber‐type‐specific molecules using mass spectrometry imaging

Cited by 16 publications

References 21 publications

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

Lipid Dynamics due to Muscle Atrophy Induced by Immobilization

m6A demethylase ALKBH5 drives denervation‐induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling

The metabolic landscape in chronic rotator cuff tear reveals tissue‐region‐specific signatures

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m⁶A demethylase ALKBH5 drives denervation‐induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling