Lipid modulation of skeletal muscle mass and function

Abstract

Loss of skeletal muscle mass is a characteristic feature of various pathologies including cancer, diabetes, and obesity, as well as being a general feature of ageing. However, the processes underlying its pathogenesis are not fully understood and may involve multiple factors. Importantly, there is growing evidence which supports a role for fatty acids and their derived lipid intermediates in the regulation of skeletal muscle mass and function. In this review, we discuss evidence pertaining to those pathways which are involved in the reduction, increase and/or preservation of skeletal muscle mass by such lipids under various pathological conditions, and highlight studies investigating how these processes may be influenced by dietary supplementation as well as genetic and/or pharmacological intervention.

Keywords: Atrophy; Catabolism; Fatty acid; Lipid; Obesity; Skeletal muscle; mTOR.

Figure 1

Disorders and conditions which are associated with reduced muscle mass and/or function. Schematic diagram illustrating various pathologies and/or conditions which are associated with increased muscle catabolism coinciding with reduced skeletal muscle mass and/or function.

Figure 2

Summary of pathways mediating muscle atrophy by saturated fatty acids. Exposure of muscle cells to saturated fatty acids such as palmitate (C16:0) results in the intracellular accumulation of toxic lipid intermediates such as ceramide and diacylglycerol. (A) Increased ceramide levels can lead to the inhibition of protein kinase B/Akt through activation of atypical protein kinase C(ξ/λ) isoforms and/or protein phosphatase 2A. Moreover, ceramide acts as a precursor for the synthesis of the glycosphingolipid GM3 which has been shown to impair insulin receptor function. In addition, ceramide may also act to modulate nutrient uptake, for example by repressing the expression of the neutral amino transporter SNAT2 thereby reducing cellular amino acid supply. (B) Diacylglycerol‐induced stimulation of protein kinase Cθ has been shown to promote serine phosphorylation of IRS‐1, resulting in its impaired function. The resulting inhibition of protein kinase B/Akt in turn can lead to the repression of protein synthesis through suppression of mechanistic target of rapamycin (mTOR)/p70‐S6 kinase 1‐dependent signalling (C), the activation of Forkhead box O (FoxO) transcription factors and induction of their target atrophic genes (D), and/or the activation of caspase‐dependent proteolysis (E). In addition, stimulation of pro‐inflammatory signalling by long chain saturated fatty acids can lead to the nuclear factor‐kappa B‐dependent upregulation of atrophic genes (F).

Figure 3

Potential mechanisms by which unsaturated fatty acids may counter obesity and/or fatty acid induced skeletal muscle atrophy. Elevated levels of saturated fatty acids and/or pro‐inflammatory cytokines, for example during obesity, can promote the development of skeletal muscle atrophy through various pathways and processes as indicated (A). Importantly, monounsaturated fatty acids and polyunsaturated fatty acids have been shown to counter these pro‐atrophic actions, which may be mediated through their ability to increase insulin sensitivity and the production of protective eicosanoids, as well as enhancing mitochondrial oxidative capacity and protein synthesis, whilst concomitantly reducing pro‐inflammatory drive (B).