Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle

Abstract

Significance: Sphingolipids are a class of bioactive lipids that regulate diverse cell functions. Ceramide, sphingosine, and sphingosine-1-phosphate accumulate in tissues such as liver, brain, and lung under conditions of cellular stress, including oxidative stress. The activity of some sphingolipid metabolizing enzymes, chiefly the sphingomyelinases, is stimulated during inflammation and in response to oxidative stress. Ceramide, the sphingomyelinase product, as well as the ceramide metabolite, sphingosine-1-phosphate, can induce the generation of more reactive oxygen species, propagating further inflammation. Recent Advances: This review article summarizes information on sphingolipid biochemistry and signaling pertinent to skeletal muscle and describes the potential influence of sphingolipids on contractile function. Critical Issues: It encompasses topics related to (1) the pathways for complex sphingolipid biosynthesis and degradation, emphasizing sphingolipid regulation in various muscle fiber types and subcellular compartments; (2) the emerging evidence that implicates ceramide, sphingosine, and sphingosine-1-phosphate as regulators of muscle oxidant activity, and (3) sphingolipid effects on contractile function and fatigue. Future Directions: We propose that prolonged inflammatory conditions alter ceramide, sphingosine, and sphingosine-1-phosphate levels in skeletal muscle and that these changes promote the weakness, premature fatigue, and cachexia that plague individuals with heart failure, cancer, diabetes, and other chronic inflammatory diseases. Antioxid. Redox Signal. 15, 2501-2517.

Redox Control of Skeletal Muscle Regeneration

“…Sphingolipids are a group of lipids playing a crucial role in cell membrane structure and lipid signaling. They may act as second messengers to stimulate oxidant production (11,241). Notably, ROS production from mitochondria has been identified as a regulator of sphingosine 1-phosphate (254).…”

17q21 locus and ORMDL3: an increased risk for childhood asthma

“…Of note is a recent description of two nonrelated children with a currently undefined metabolic defect and encephalopathy characterized by low serine concentrations (the substrate for SPT) in serum and CSF, both of whom were also suffered from severe asthma (64). Sphingolipids affect the force of skeletal muscle contraction (65,66) and smooth muscle proliferation (67). The effect of altered cellular sphingolipids on airway smooth muscle cells is not known.…”

Triangulated Mal-Signaling in Alzheimer's Disease: Roles of Neurotoxic Ceramides, ER Stress, and Insulin Resistance Reviewed

“…Reversal of the sphingomyelin synthesis reaction can also generate ceramides. Sphingomyelinases, which increase ceramide levels by stimulating sphingomyelin hydrolysis, are activated by various drugs, physical agents, and natural compounds, including chemotherapeutic agents, pro-inflammatory cytokines, e.g., TNF-α, endotoxins, trophic factor withdrawal, heat, ionizing radiation, Fas, and 25-dihydroxy-vitamin D 3 [41, 43, 56, 72, 81, 84, 85]. …”

“…Moreover, sphingoid bases released from lysosomes may possess unique or independent biological functions. Finally, sphingosine-1-phosphate is an important biologically active metabolite that can only be generated from free sphingosine [85]. Therefore, the regulation of ceramide synthesis, levels, and actions is central to many cellular and biological processes.…”