Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation

Abstract

Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2α phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2α phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.

Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

“…T2D is characterised by reduced numbers of predominantly oxidative type I fibres and increased numbers of predominantly glycolytic type II fibres (Oberbach et al 2006), with the proportion of type I fibres correlating positively with insulin sensitivity (Stuart et al 2013). Ageing also results in a preferential reduction in the size of type II fibres (Lexell 1995), and the net result is that reduced mitochondrial activity (Johannsen et al 2012) and IR (Groen et al 2014, Tardif et al 2014) may also be evident in muscle. In summary, it appears that IR, loss of muscle mass and changes in muscle fibre type all have the potential to independently or additively alter whole-body glucose homeostasis with ageing.…”

“…In addition, studies of animal models of SO demonstrating pathophysiological or molecular mechanisms pertinent to the development of the syndrome in humans have rarely been reported. However, some researchers have studied aged rats with diet-induced obesity (Bollheimer et al 2012, Tardif et al 2014, whereas obese Zucker rats are characterised by marked obesity, IR and generalised muscle atrophy (Nilsson et al 2013), and thus may be useful for the study of SO at a younger age. …”

“…Increased IMCL has also been associated with impaired muscle function in a number of studies. Lipid infusion results in reduced protein synthesis in response to both amino acids and insulin in healthy human volunteers (Stephens et al 2015), whereas diet-induced obesity and ectopic deposition of lipid in muscle rather than adipose tissue are also associated with impaired protein synthesis in rodents (Anderson et al 2008, Masgrau et al 2012, Tardif et al 2014. This is associated with increased phosphorylation of elongation factor 2B, a key mediator of ribosomal protein synthesis, in rodent muscle and a saturated fatty acid (SFA)/ceramide-induced increase in elongation factor 2α activation in cultured muscle cells (Tardif et al 2014).…”

From Sarcopenia to Frailty: The Pathophysiological Basis and Potential Target Molecules of Intervention

“…Age-related sarcopenia is associated with an increase in abdominal obesity, which refers to sarcopenic obesity [57]. Sarcopenic obesity leads to the infiltration of fat into the muscle and the accumulation of triglycerides within the cell, which impairs the function of the insulin receptor substrate causing insulin resistance, a lower lipid buffering capacity, and anabolic resistance in muscle [23,58]. Sarcopenic obesity also results in cognitive impairment because of insulin resistance.…”

“…Lifestyle interventions play critical roles in the prevention of sarcopenia, frailty, and cognitive impairment. Physical exercise, particularly resistance exercise, can improve muscle mass and strength in the elderly [64,65] and obese elderly [58]. Individuals with higher initial adiposity experience less improvement in both muscle strength and physical function [66].…”