February 2013

The sphingolipid connection in muscle weakness

The metabolism of sphingolipids is subject to regulation and generates bioactive metabolites that mediate the cellular response to stress. Emerging research suggests that sphingolipids also influence the force of skeletal muscle contraction (1). These studies add to the well-characterized role of sphingolipids in the regulation of glucose uptake by muscle (2). A complex and essential role is becoming apparent for specific bioactive metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate and a distinct set of related metabolic enzymes.

Contraction of skeletal muscles is caused by neurally activated sarcolemmal action potentials, which propagate throughout the cells, causing calcium release from intracellular stores and activation of myofilament proteins. In part, the amplitude of these calcium transients determines the force of contraction.

Sphingosine and sphingosine-1-phosphate have opposing effects on calcium transients. Sphingosine (and to a lesser extent dihydrosphingosine and phytosphingosine) directly binds to and inhibits the sarcolemmal calcium channel. In contrast, sphingosine-1-phosphate acts via G(i)-coupled, agonist-specific surface receptors S1P3 and S1P2 to increase cytosolic calcium levels from both extracellular and intracellular pools.

Cancer, aging and other pro-inflammatory processes are associated with a persistent decline in the force of muscle contraction. Several findings suggest that sphingolipids — more specifically ceramide — promote muscle weakness:

  •   (i) Direct exposure to sphingomyelinase or cell-permeable ceramide depresses the force of intact fiber bundles from murine diaphragm ex vivo (3).
  •  (ii) TNF, a systemic mediator of weakness, causes abrupt accumulation of C18, C20 and C22 ceramides in muscle.
  • (iii) Exercise can ameliorate muscle weakness and also alters sphingolipid metabolism, a complex effect that varies with exercise duration and muscle type.

The mechanisms by which sphingolipids regulate muscle force have begun to emerge. Beyond modulating calcium, sphingolipids appear to stimulate oxidant production and depress myofilament function. Sphingomyelinase exposure increases ceramide levels, increases cytosolic oxidant activity and depresses the force of muscle fiber bundles. Antioxidant pretreatment blunts the force decrement, identifying oxidants as downstream mediators of sphingomyelinase action. Studies of permeabilized fibers suggest these oxidants depress force via effects on myofilament proteins (4).

At the same time, key questions remain unanswered. More and more data suggest that sphingosine rather than ceramide is the direct mediator of weakness. Systematic analyses of the enzymes that mediate ceramide turnover in muscle will help resolve this dilemma. Furthermore, skeletal muscle fibers have a highly specialized structure. Subcellular localization of the enzymes that regulate sphingolipid metabolism appears to be critical but remains to be defined. Such studies may reveal novel aspects of sphingolipid metabolism and identify downstream targets that are specific to muscle.

  1. 1. Nikolova-Karakashian, M. N. & Reid, M. B. Antioxid. Redox. Signal. 9: 2501 – 2517 (2011).
  2. 2. Chavez, J. A. & Summers, S. A. Cell Metab. 5, 585 – 594 (2012).
  3. 3. Ferreira, L. F. et al. Am. J. Physiol. Cell. Physiol. 3, C552 – C560 (2010).
  4. 4. Ferreira, L. F. et al. J. Appl. Physiol. 9, 1538 – 1545 (2012).

Mariana Nikolova-KarakashianMichael ReidMariana Nikolova-Karakashian (mnikolo@uky.edu) is a professor in the physiology department at the University of Kentucky. Michael Reid (michael.reid@uky.edu) is the Shih-Chun Wang professor and chair of the physiology department at the University of Kentucky.

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