A Possible Link Between Skeletal Muscle Mitochondrial Efficiency and Age-Induced Insulin Resistance

Abstract

The transition from young to adult age is associated with decreased insulin sensitivity. To investigate whether changes in skeletal muscle mitochondrial function could be involved in the development of insulin resistance, we measured the oxidative capacity and energetic efficiency of subsarcolemmal and intermyofibrillar mitochondria isolated from the skeletal muscle of 60-and 180-day-old rats. Mitochondrial efficiency was tested by measuring the degree of thermodynamic coupling and optimal thermodynamic efficiency, as well as mitochondrial proton leak, which was determined in both the absence (basal) and the presence (fatty acid induced) of palmitate. Serum glucose, insulin, and HOMA index were also measured. The results show that in adult rats, concomitant with increased HOMA index, skeletal muscle mitochondria display higher respiratory capacity and energy efficiency. In fact, thermodynamic coupling and optimal thermodynamic efficiency significantly increased and fatty acid-induced proton leak was significantly lower in the skeletal muscle mitochondria from adult than in younger rats. A deleterious consequence of increased mitochondrial efficiency would be a reduced utilization of energy substrates, especially fatty acids, leading to intracellular triglyceride accumulation and lipotoxicity, thus contributing to the onset of skeletal muscle insulin resistance. Diabetes 53: 2861-2866, 2004 I ncreasing age is associated with obesity and insulin resistance not only in humans but also in rodents (1-5). In fact, ad libitum-fed caged rats are a good animal model that simulates the situation (sedentary lifestyle and unrestricted diet) of people in the western world.It has been previously shown that age-induced insulin resistance in rats is already detectable at 4 months of age, concomitant to a rapid rise in fat mass, and does not further increase later in life (3). This early decrease in insulin sensitivity could in turn lead to the metabolic disturbance typical of old age.Our previous results also indicate that in the transition from postpubertal (60 days) to adult (180 days) age, rats display reduced sensitivity to the anorexic effect of leptin (6) and, at the cellular level, hepatic mitochondrial machinery shows some age-related biochemical impairment (7,8). From all the above findings, it can be deduced that adult rats can be considered a good experimental tool for studying the onset of the "aging" phenomenon.It has been postulated that defects in mitochondrial performance could contribute to the development of insulin resistance (9), and mitochondrial oxidative capacity has been considered a good predictor of insulin sensitivity (10). These suggestions are not surprising since control of mitochondrial respiration and oxidative phosphorylation is fundamental for the maintenance of cellular homeostasis. The above control is exerted at two levels, i.e., regulation of the rate of oxygen consumption and ATP production and regulation of oxidative phosphorylation efficiency (11). The main determinant of oxidative phosp...

Aging impairs insulin-stimulated glucose uptake in rat skeletal muscle via suppressing AMPKα

“…For example, it was showed animals treated with R-etomoxir, an inhibitor of CPT-1, the key enzyme of intracellular fatty acid beta-oxidation, became more insulin resistant (Dobbins et al, 2001), while those with CPT-1 over-expression exhibited significantly increased insulin sensitivity (Perdomo et al, 2004). Aging is also associated with impaired intracellular fatty acid oxidation (Calles-Escandon et al, 1995, 1997Park et al, 2006), and this was proposed as an important mechanism underlying age-related insulin resistance (Petersen et al, 2003;Cree et al, 2004;Iossa et al, 2004;Menshikova et al, 2006;Slawik and Vidal-Puig, 2006). However, the mechanisms are still unclear.…”

“…Recent researches have proposed that insufficient intracellular fatty acid oxidation and subnormal triglyceride (TG) accumulation in insulin target organs might be an important contributor (Cree et al, 2004;Iossa et al, 2004;Menshikova et al, 2006;Slawik and Vidal-Puig, 2006). Although the effects of aging on impaired fatty acid oxidation and fat accumulation have been well demonstrated in both humans and rodents (CallesEscandon et al, 1995(CallesEscandon et al, ,1997Park et al, 2006), the mechanism underlying is unclear.…”

Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis

“…16 In addition, a significant direct relationship between skeletal muscle oxidative capacity and insulin sensitivity has been found. 54 In a previous work, we found a possible link between skeletal muscle mitochondria and insulin resistance in another obesity model, such as ageing, 32 and therefore it could be suggested that the alteration of mitochondrial function is a common cause of insulin resistance development in different obesity models. However, the underlying mechanisms appear to be different.…”

“…32 Mitochondrial oxygen consumption and membrane potential were titrated at 301C by sequential additions of malonate up to 3 mM for IMF and 5 mM for SS mitochondria. Measurements were carried out in a medium containing 30 mM LiCl, 6 mM MgCl 2 , 75 mM sucrose, 1 mM EDTA, 20 mM Tris-PO 4 , pH 7.0, succinate (10 mM), rotenone (3.75 mM), oligomycin (2 mg/ml), safranin O (83.3 nmol/mg), nigericin (80 ng/ml) and 0.1% (w/v) fatty acid free BSA.…”

Altered Skeletal Muscle Subsarcolemmal Mitochondrial Compartment During Catch-Up Fat After Caloric Restriction

“…, and calibration curves made for each preparation as previously reported (18). Measurements were carried out at 30°C in a medium containing 30 mmol/l LiCl, 6 mmol/l MgCl 2 , 75 mmol/l sucrose, 1 mmol/l EDTA, 20 mmol/l Tris-P, pH 7.0, and 0.1% (wt/vol) BSA in the presence of succinate (10 mmol/l), rotenone (3.75 mol/l), oligomycin (2 g/ml), safranin O (83.3 nmol/mg), and nigericin (80 ng/ml).…”