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.

β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle

“…Despite being necessary to cellular health, ceramides mediate multiple pathological cellular processes [17,18,19], including forcing sustained mitochondrial fission [8]. Due to our findings of reduced mitochondrial fission in myotubes following β-HB treatment, we probed ceramide levels and found a small but significant reduction in multiple ceramide species, including C16, C22 and C24 (Figure 4).…”

“…We previously found that mitochondrial morphology alters mitochondrial physiology, including respiration and reactive oxygen species production [8]. In an effort to better understand a potential non-energetic mechanism whereby β-HB alters mitochondrial respiration, we scrutinized mitochondrial morphology and amount in C2C12 myotubes following β-HB treatment.…”

“…Disrupted mitochondrial function is thought to at least contribute to muscle insulin resistance [8,9], likely due to increased oxidative stress and altered insulin signaling [10,11,12], both of which may be affected by changes in mitochondrial morphology [8]. …”

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…First, there is evidence that ceramides accumulate within the skeletal muscle and promote the oxidative stress and mitochondrial dysfunction (Coen & Goodpaster, 2012; Smith et al ., 2013). Second, the accumulation of ceramide within the myocardium (lipotoxicity) has been recently proposed as a major cause of dilated cardiomyopathy in patients with diabetes and obesity and as a potential mechanism for the development of heart failure, even in the absence of hypertension and myocardial ischemia Park and Goldberg, 2012.…”

Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system?

“…This has been associated with the development of insulin resistance as well as altered mitochondrial respiratory activity (50,132). Importantly, administration of pharmacological inhibitors of de novo ceramide synthesis [e.g., the serine palmitoyltransferase (SPT) inhibitor myriocin] has been shown to ameliorate the insulin-desensitizing effects of dietinduced obesity as well as promote improvements in whole body oxygen consumption and mitochondrial function (146,156).…”