Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle
Abstract
Ceramide is a sphingolipid that serves as an important second messenger in an increasing number of stress-induced pathways. Ceramide has long been known to affect the mitochondria, altering both morphology and physiology. We sought to assess the impact of ceramide on skeletal muscle mitochondrial structure and function. A primary observation was the rapid and dramatic division of mitochondria in ceramide-treated cells. This effect is likely to be a result of increased Drp1 (dynamin-related protein 1) action, as ceramide increased Drp1 expression and Drp1 inhibition prevented ceramide-induced mitochondrial fission. Further, we found that ceramide treatment reduced mitochondrial O2 consumption (i.e. respiration) in cultured myotubes and permeabilized red gastrocnemius muscle fibre bundles. Ceramide treatment also increased H2O2 levels and reduced Akt/PKB (protein kinase B) phosphorylation in myotubes. However, inhibition of mitochondrial fission via Drp1 knockdown completely protected the myotubes and fibre bundles from ceramide-induced metabolic disruption, including maintained mitochondrial respiration, reduced H2O2 levels and unaffected insulin signalling. These data suggest that the forced and sustained mitochondrial fission that results from ceramide accrual may alter metabolic function in skeletal muscle, which is a prominent site not only of energy demand (via the mitochondria), but also of ceramide accrual with weight gain.
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Treatment of muscle cells with cell permeable ceramide C2 induces mitochondrial fission underpinned by upregulation of dynamin-related protein 1.
“Particularly, treatment of muscle cell with the cell permeable ceramide C2 induced mitochondrial fission underpinned by the upregulation of dynamin-related protein 1.”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Smith et al., 2013
Ceramide may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.
“indicating that this lipotoxic metabolite may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Smith et al., 2013
The detrimental effect of ceramide on mitochondrial bioenergetics and dynamics as well as insulin signalling is prevented by inhibiting mitochondrial fission.
“Remarkably, the detrimental effect of ceramide on mitochondrial bioenergetics and dynamics as well as insulin signalling were prevented by inhibiting mitochondrial fission (Smith et al., 2013).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Smith et al., 2013
In skeletal muscle, reduced mitochondrial respiration has been linked to aberrant control of mitochondrial dynamics.
“In skeletal muscle, reduced mitochondrial respiration has also been linked to aberrant control of mitochondrial dynamics [64–67].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [67]
Increased exposure of myotubes to PA and fatty acid derivatives such as ceramide promotes a low mitochondrial fusion to fission ratio, resulting in fragmented, discontinuous mitochondria that exhibit diminished capacity for respiration and ATP synthesis and are thought to be causally linked to impaired insulin sensitivity and metabolic function.
“Increased exposure of myotubes to PA and fatty acid derivatives such as ceramide promote a low mitochondrial fusion to fission ratio resulting in fragmented, discontinuous mitochondria that not only exhibit diminished capacity for respiration and ATP synthesis, but also is thought to be causally linked to impaired insulin sensitivity and metabolic function [66–68].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [67]
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Self-citation
- Authors
- Smith, M. E., Tippetts, T. S., Brassfield, E. S., Tucker, B. J., Ockey, A., Swensen, A. C., Anthonymuthu, T. S., Washburn, T. D., Kane, D. A., Prince, J. T., & Bikman, B. T.
- Affiliations
- Brigham Young University (US)
- St. Francis Xavier University (CA)
- Corresponding author
- Ockey, Adelaide
- ORCID
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2013-11-22
- Volume
- 456
- Issue
- 3
- Pages
- 427-439
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2324271348
- Cited by
- 87
- References
- 49
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 7
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- ceramide, mitochondrial fission, Drp1, skeletal muscle, mitochondrial respiration, oxidative stress, hydrogen peroxide, insulin signaling, myotubes, sphingolipids, metabolic disruption
- MeSH terms
- Animals, Cell Line, Ceramides, Hydrogen Peroxide, Insulin, Male, Mitochondria, Muscle, Oxygen Consumption, Phosphorylation, Signal Transduction, Muscle Fibers, Skeletal, Dynamins, Proto-Oncogene Proteins c-akt, Mice, Mitochondrial Dynamics
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