Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Chrast, Roman; Saher, Gesine; Nave, Klaus Armin; Verheijen, Mark H. G.

doi:10.1194/jlr.r009761

Cited by 236 publications

(253 citation statements)

References 169 publications

(174 reference statements)

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“…This could partially explain the stronger defects observed in OLs‐Raptor/Rictor double mutants (Lebrun‐Julien et al, 2014). Intriguingly, at least in yeast, mTORC2 has been already linked to the biosynthesis of sphingolipids (Aronova et al, 2008), a lipid class highly represented in myelin (Chrast, Saher, Nave, & Verheijen, 2011). …”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

129

120

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

129

120

View full text Add to dashboard Cite

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“…First, sphingolipids modulate the physical properties of membranes, including their fluidity, thickness, and curvature. These attributes underlie the key functions of sphingolipids in myelin (Chrast et al 2011) and the epidermal barrier (Feingold 2009). These properties also enable sphingolipids to influence the activity and spatial organization of membrane proteins (Lingwood and Simons 2010).…”

Section: Sphingolipid Modes Of Actionmentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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“…Since myelin integrity is highly affected in numerous lipid metabolic disorders (reviewed in Ref. 7), reduction of FFA as in ATGL Ϫ/Ϫ mice could compromise its function. Another possible explanation is a mechanical contraction defect in the muscle filaments due to excessive IMCL accumulation and extremely large LDs in ATGL Ϫ/Ϫ muscles.…”

Section: Increased Imcl Deposition In Skeletal Muscle Of Atglmentioning

confidence: 99%

Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice

Nunes

Weijer

Veltien

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Adipose triglyceride lipase (ATGL) is a lipolytic enzyme that is highly specific for triglyceride hydrolysis. The ATGL-knockout mouse (ATGL−/−) accumulates lipid droplets in various tissues, including skeletal muscle, and has poor maximal running velocity and endurance capacity. In this study, we tested whether abnormal lipid accumulation in skeletal muscle impairs mitochondrial oxidative phosphorylation, and hence, explains the poor muscle performance of ATGL−/− mice. In vivo 1H magnetic resonance spectroscopy of the tibialis anterior of ATGL−/− mice revealed that its intramyocellular lipid pool is approximately sixfold higher than in WT controls ( P = 0.0007). In skeletal muscle of ATGL−/− mice, glycogen content was decreased by 30% ( P < 0.05). In vivo 31P magnetic resonance spectra of resting muscles showed that WT and ATGL−/− mice have a similar energy status: [PCr], [Pi], PCr/ATP ratio, PCr/Pi ratio, and intracellular pH. Electrostimulated muscles from WT and ATGL−/− mice showed the same PCr depletion and pH reduction. Moreover, the monoexponential fitting of the PCr recovery curve yielded similar PCr recovery times (τPCr; 54.1 ± 6.1 s for the ATGL−/− and 58.1 ± 5.8 s for the WT), which means that overall muscular mitochondrial oxidative capacity was comparable between the genotypes. Despite similar in vivo mitochondrial oxidative capacities, the electrostimulated muscles from ATGL−/− mice displayed significantly lower force production and increased muscle relaxation time than the WT. These findings suggest that mechanisms other than mitochondrial dysfunction cause the impaired muscle performance of ATGL−/− mice.

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Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Cited by 236 publications

References 169 publications

Myelination and mTOR

Myelination and mTOR

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice

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