Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins

Abstract

Skeletal muscle is one of the main regulators of carbohydrate and lipid metabolism in our organism, and therefore, it is highly susceptible to changes in glucose and fatty acid (FA) availability. Skeletal muscle is an extremely complex tissue: its metabolic capacity depends on the type of fibers it is made up of and the level of stimulation it undergoes, such as acute or chronic contraction. Obesity is often associated with increased FA levels, which leads to the accumulation of toxic lipid intermediates, oxidative stress, and autophagy in skeletal fibers. This lipotoxicity is one of the most common causes of insulin resistance (IR). In this scenario, the “isolation” of certain lipids in specific cell compartments, through the action of the specific lipid droplet, perilipin (PLIN) family of proteins, is conceived as a lifeguard compensatory strategy. In this review, we summarize the cellular mechanism underlying lipid mobilization and metabolism inside skeletal muscle, focusing on the function of lipid droplets, the PLIN family of proteins, and how these entities are modified in exercise, obesity, and IR conditions.

Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

“…As the downregulation of PPARG expression and transcriptional activity is associated with the development of insulin resistance (54) and many PPAR transcriptional targets are mitochondrial lipid transport proteins (21), we propose that a decreased capacity for mitochondrial lipid import may contribute to the observed phenotype of BC-induced lipid accumulation, which may then contribute to insulin resistance. Finally, aberrant intramyocellular lipid deposition can in many cases contribute to lipotoxicity characterized by the accumulation of toxic lipid intermediates such as diacylglycerols and ceramides (55), increased production of ROS (56), and is associated with changes in autophagic dynamics (57,58), all of which are implicated in reduced mitochondrial function within skeletal muscle. The sum of these observations suggest that skeletal muscle lipotoxicity in breast cancer could play a major role in the phenotype of BC induced skeletal muscle fatigue independent of mitochondrial dysfunction, and future studies should investigate this potential link in greater detail.…”

Obesity leads to impairments in the morphology and organization of human skeletal muscle lipid droplets and mitochondrial networks, which are resolved with gastric bypass surgery‐induced improvements in insulin sensitivity

“…Intramyocellular lipids are stored in lipid droplets (LDs), composed of an inner core of neutral lipids and sterol esters surrounded by a monolayer of phospholipids and coating proteins, including members of the perilipin (PLIN) protein family (For review, see ref. 6). Skeletal muscle predominantly expresses PLIN2, 3 and 5.…”

RabGAPs in skeletal muscle function and exercise

“…As already mentioned in a chapter above, accumulation of toxic lipid intermediates such as DAGs in skeletal muscle impair muscular insulin sensitivity by inhibiting the insulin signaling cascade and consequently, GLUT4 translocation (Ragheb et al 2009, Boucher et al 2014, Morales et al 2017). Exercise has a prophylactic effect on lipid-induced insulin resistance.…”

“…Skeletal muscle lipid utilization is of high relevance for the maintenance of a metabolic flexible state and thus may prevent insulin resistance and ectopic lipid accumulation. Accumulation of toxic lipid intermediates such as diacylglycerols (DAGs) and ceramides in skeletal muscle are known to impair muscular insulin sensitivity by inhibiting the insulin signaling cascade, a process described as 'lipotoxocity' (Ragheb et al 2009, Boucher et al 2014, Morales et al 2017. Both TBC1D1 and TBC1D4 have been implicated to exert an important function in skeletal muscle lipid use; therefore, these two factors can be considered as signaling hubs between glucose and lipid metabolism.…”