Age-Related Decline of Skeletal Muscle Insulin Sensitivity in Rats: Effect of Sex and Muscle Type

Abstract

Aging is associated with a progressive decline of skeletal muscle function and insulin sensitivity. Sex differences in the insulin response to different physiological situations have been found, leading to the development of type 2 diabetes. The aim of this study was to investigate the changes in insulin sensitivity with age in male and female rats and to elucidate whether there are sex differences in the alteration profiles of systemic insulin sensitivity parameters, adiposity, skeletal muscle oxidative damage, and the insulin signaling pathway. The gastrocnemius and soleus muscles of male and female rats of 3, 9, and 18 months of age were used. The decrease of insulin sensitivity with age was higher in female than in male rats. However, the increase of both serum insulin levels and adiposity with age shows a different profile in both sexes and suggests an earlier onset of age-related impairment of insulin sensitivity in male than in female rats. Sex differences in insulin signaling key protein levels were found mainly in the most aged rats, suggesting that sex differences in these proteins would be manifested at more advanced ages than differences in the insulin-sensitivity serum profile. In addition, the gastrocnemius muscle showed more age-associated oxidative damage and insulin resistance impact than the soleus in both sexes. These results suggest the sex differences found in the impairment of insulin sensitivity of aged rats would not be attributable to differences between sexes in the time course of the levels of key proteins of the skeletal muscle insulin signaling pathway, at least in the first 18 months of life.

Obesity improves myocardial ischaemic tolerance and RISK signalling in insulin-insensitive rats

“…OB rats also exhibited elevated triglycerides, with comparable insulin and glucose compared with lean CD rats. Consistent with prior studies, 10-month-old Wistar rats displayed elevated serum insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels compared with 3-month-old rats (Gómez-Pérez et al, 2011; Gu et al, 2011). Serum insulin levels in young rats were 50% of those in 10-month-old CD and OB rats (3.04±0.10 versus 6.70±0.18 and 6.86±0.11 ng/ml in young versus old CD and OB rats, respectively).…”

“…This approach permits analysis of the effects of obesity overlaid upon common insulin-insensitivity in older animals. The majority of ischaemic heart disease patients are elderly (more than 70% of sufferers are >65 years of age), and age also impairs insulin-sensitivity in animals (Gómez-Pérez et al, 2011; Gu et al, 2011) and humans (Pagano et al, 1981). Because myocardial resistance to I-R injury depends in part upon functionality of reperfusion injury salvage kinase (RISK) pathway components (Downey et al, 2007; Halestrap et al, 2007; Hausenloy and Yellon, 2009), , including Akt, which is also key to insulin signalling (Bertrand et al, 2008), and because reversal of the negative effects of insulin-resistance is linked to improved RISK and nitric oxide synthase (NOS) signalling (Bulhak et al, 2009; Huisamen et al, 2011), we tested the hypothesis that obesity modifies myocardial I-R tolerance via shifts in pro-survival RISK-NOS signalling in insulin-insensitive rats.…”

Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner

“…Taken together, both the present (performed in 9-month-old rats) and the aforementioned studies suggest the existence of age-dependent sex differences in the capacity to induce UCP3 expression in response to HFD feeding. Our results also suggest that, given the proposed role of UCP3 in the regulation of insulin sensitivity [39], male rats would decrease their capacity to induce gastrocnemius UCP3 expression in response to HFD feeding between 9 and 18 months of age, in accordance with their higher oxidative damage and the earlier impairment of insulin sensitivity that male rats undergo with age compared to females [40]. …”

Ablation of the Id2 Gene Results in Altered Circadian Feeding Behavior, and Sex-Specific Enhancement of Insulin Sensitivity and Elevated Glucose Uptake in Skeletal Muscle and Brown Adipose Tissue

“…Considering the total mass of skeletal muscle in the body, a small difference in glucose uptake in the forelimb muscle could be indicative of a highly elevated glucose uptake by total skeletal muscle in Id2−/− males. Furthermore, insulin resistance in skeletal muscle is associated with aging [20], [38], [39], and sexual dimorphism is observed in the development of insulin resistance [40], [41]. Since Id2 expression in the skeletal muscle is reported to increase during aging [42], it is possible that the difference between Id2−/− and WT males in skeletal muscle glucose uptake also increases with age.…”