Diet-induced obesity alters signalling pathways and induces atrophy and apoptosis in skeletal muscle in a prediabetic rat model

Abstract

Pro-inflammatory and stress-activated signalling pathways are important role players in the pathogenesis of obesity and insulin resistance. Obesity and type II diabetes are associated with chronic, low-grade inflammation and elevated tumour necrosis factor-α (TNF-α) levels. There is increasing evidence that TNF-α may play a critical role in skeletal muscle atrophy. However, the effects of obesity-induced insulin resistance on these signalling pathways are poorly understood in skeletal muscle. Therefore, the present study addressed the effects of obesity-induced insulin resistance on the activity of the ubiquitin ligases, nuclear factor-κB, p38 MAPK and phosphoinositide 3-kinase signalling pathways in the gastrocnemius muscle and compared these with muscle of standard chow-fed control rats. Male Wistar rats were randomly allocated to a control diet group (standard commercial chow; 60% carbohydrates, 30% protein and 10% fat) or a cafeteria diet group (65% carbohydrates, 19% protein and 16% fat) for 16 weeks. Blood analysis was conducted to determine the impact of the model of obesity on circulating insulin, glucose, free fatty acids, TNF-α and angiotensin II concentrations. The experimental animals were 18% heavier and had 68% greater visceral fat mass than their control counterparts and were dyslipidaemic. Significant increases in the ubiquitin ligase and MuRF-1, as well as in caspase-3 and poly-ADP-ribose polymerase cleavage were observed in the muscle of obese animals compared with the control rats. We propose that dyslipidaemia may be a mechanism for the activation of inflammatory/stress-activated signalling pathways in obesity and type II diabetes, which will lead to apoptosis and atrophy in skeletal muscle.

The effects of high fat diet and moderate exercise on TGFβ1 and collagen deposition in mouse skeletal muscle

“…However, findings are more inconsistent when studying muscle atrophy and fiber size in high fat diet-induced obesity models. Sishi and colleagues found that 16 weeks of Western diet resulted in decreased fiber CSA in rats [6]. Shortreed et al [35] however, reported increased fiber CSA in soleus muscle after 8 weeks of 60% fat diet.…”

“…In addition to inhibiting insulin signaling, obesity and/or HF diet can have detrimental effects on skeletal muscle structure and function, including fibrosis, atrophy associated with reductions in myofiber cross sectional area and total muscle mass, decreased strength, and impaired regeneration in response to injury [6][7][8]. Fibrosis is the excessive accumulation of matrix proteins, and collagen is the most abundant protein deposited in tissue in response to injury [9].…”

The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass

“…While up-regulation of MAFbx and MuRF-1 was demonstrated in experimental models of food deprivation, over feeding has also been reported to affect their expression [87].…”

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

“…Macrophage infiltration has also been demonstrated by a number of groups (Hevener et al 2007, Fink et al 2014, but not all (Tam et al 2012), to be a feature of obesity-associated IR in skeletal muscle, and a synergistic interaction between macrophages and fatty acids that leads to impaired muscle insulin action has been reported (Varma et al 2009). However, an alternative proposal is that dyslipidaemia associated with obesity activates cellular stress signalling pathways and thereby apoptosis and atrophy in skeletal muscle (Sishi et al 2011). In particular, SFA can specifically induce pro-inflammatory macrophage activation and consequent p38 MAPK-mediated IR in cultured myotubes, an effect that is ameliorated by the UFA palmitoleate (Talbot et al 2014).…”