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Muscle fat oxidative capacity is not impaired by age but by physical inactivity: association with insulin sensitivity ¹

VIRGINIE RIMBERT^*, YVES BOIRIE^*, MARIO BEDU, JEAN-FRANÇOIS HOCQUETTE, PATRICK RITZ and BÉATRICE MORIO^*,2

^* Protein and Energy Metabolism Research Unit,
Laboratory of Physiology and Biology of Sport, Auvergne University, Human Nutrition Research Centre of Auvergne, Clermont-Ferrand, France;
INRA, Ruminant Research Unit, Saint-Genès-Champanelle, France; and
Unit of Clinical Gerontology, University Hospital, Angers, France

² Correspondence: Protein and Energy Metabolism Research Unit, Human Nutrition Laboratory, BP 321, 58 Montalembert Str., 63009 Clermont-Ferrand cedex 1, France. E-mail: morio{at}clermont.inra.fr

SPECIFIC AIMS

Insulin resistance in skeletal muscle is a major factor in the pathogenesis of type 2 diabetes. Petersen et al. recently proposed that age-induced dysfunction in muscle mitochondria may be crucial in the etiology of insulin resistance. Whether these mitochondrial alterations are the consequences of age per se or of physical inactivity remains to be determined.

The first aim (study 1) was to examine whether muscle mitochondrial functions and fat oxidative capacity are impaired by age per se or by changes in life style and whether they are associated with reduced insulin sensitivity. We investigated four groups of young and elderly healthy subjects rigorously selected by physical activity. Sixteen healthy, nonobese elderly men (66.9±3.4yr) and 16 healthy nonobese young men (24.6±2.8yr) participated in the first study (Table 1 ).In the two age groups, 10 subjects were sedentary (i.e., did not participate in regular physical exercise program) and 6 regularly practiced one or several endurance activities >5 h/wk.

The second aim (study 2) was to investigate whether endurance training could result in a parallel improvement in muscle fat oxidative capacity and insulin sensitivity in 8 healthy nonobese elderly sedentary people (5 men and 3 postmenopausal women, 63.5±3.3 year; Table 2 )in order to confirm that physical activity-induced increase in muscle fat oxidative capacity is closely associated with enhanced insulin sensitivity in healthy individuals.

PRINCIPAL FINDINGS

1. Study 1
Muscle fat oxidative capacity (i.e., total oxidation rate of [1-¹⁴C]palmitate; Table 1 ) was 45.7% higher in active subjects than in sedentary individuals (P<0.0001) but was similar between young and elderly individuals (P=NS). Similar results were obtained for the maximal activity of mitochondrial key enzymes. The maximal activity of carnitine palmitoyltransferase I, ß-hydroxyacyl-CoA dehydrogenase, citrate synthase, and respiratory chain complexes II, III, and IV was significantly reduced by 25–55% in sedentary subjects vs. active individuals (P<0.05–0.0001). It was similar among age groups (P=NS) except for the maximal activity of citrate synthase, which was decreased by 22% in elderly volunteers vs. young subjects (P<0.05).

The insulin sensitivity index was calculated from a 3 h oral glucose tolerance test (75 g glucose) (Table 1) . It was significantly higher in active than in sedentary individuals, but similar between young and elderly groups. Stepwise regression was performed to determine which variables among body composition, VO_2max, muscle enzyme activities, and muscle palmitate oxidative capacity contributed to variation in the insulin sensitivity index. Analysis showed that muscle palmitate oxidative capacity (variance explained=33.4%; P<0.001) and % truncal fat (variance=12.4%; P<0.05) were the main predictors of the insulin sensitivity index (R²=0.458; P<0.001). The correlation between muscle fat oxidative capacity and insulin sensitivity index is illustrated in Fig. 1 .

View larger version (26K): [in this window] [in a new window]   Figure 1. Correlation between muscle fat oxidative capacity and insulin sensitivity index in young and elderly, sedentary, and active males (n=6 per active group; n=10 per sedentary group). Insulin sensitivity index was calculated using equations from A) Matsuda and DeFronzo, B) Soonthornpun et al., C) Belfiore et al., and D) Cederholm and Wibell.

2. Study 2
Endurance training (supervised cycling on a cycloergometer 3 times/wk for 8 wk) induced significant improvements in VO_2max and body composition (fat-free mass gain, fat mass loss). Muscle fat oxidative capacity increased by 22.0 ± 26.6% with training (–4.1 to +76.9%; P<0.05). Insulin sensitivity evidenced by insulin-mediated glucose disposal (IMGD), measured during a 3 h insulin clamp, increased by 33.7 ± 32.4% with training (–7.5 to +97.8%; P<0.05). Training-induced changes in IMGD were positively correlated with increases in muscle palmitate oxidative capacity (r=0.79; P<0.01).

SIGNIFICANCE AND CONCLUSIONS

The principal conclusion from this experiment was that muscle mitochondrial functions and the resultant muscle fat oxidative capacity and insulin sensitivity were not impaired primarily by age but by physical inactivity. Even in healthy people, insulin sensitivity was mainly determined by muscle fat oxidative capacity. It was less tightly negatively correlated with % truncal fat mass. Therefore, these results support the hypothesis that muscle mitochondrial function (more specifically, muscle ability to oxidize fat) is an important regulator of insulin sensitivity. To reinforce this conclusion, we showed in sedentary elderly subjects that muscle fat oxidative capacity and insulin sensitivity improved in parallel after 8 wk of endurance training. Consequently, interventions like physical activity or pharmacological agents able to modulate oxidative capacities might be proposed to prevent metabolic disorders.

The major difficulty in studying the effect of aging on muscle functions is to distinguish between the effects of age per se from the consequences of a natural decline in physical activity. The strength of our demonstration is based on the fact that in the first study we matched young and elderly people according to their physical training and VO_2max.kg FFM^–1 while taking into account the physiological age-related decrease in VO_2max. In agreement with others, our data confirmed that muscle mitochondrial function and the resultant muscle fat oxidative capacity are not altered by age per se, and are maintained through sustained physical activity in the elderly. Therefore, our data provide additional evidence that the age-related decline in muscle mitochondrial function often described in a normal population may be due primarily to a reduction in physical activity.

We observed that insulin sensitivity is not significantly impaired by age when the level of physical activity is taken into account. This finding is controversial, since most studies have described a reduction in peripheral tissue insulin sensitivity with aging. As for muscle mitochondrial function, the main difficulty in studying the effect of aging on peripheral insulin sensitivity is to distinguish between the effects of age per se and the consequences of sedentary behavior. Our data demonstrate that the age-related decline in insulin sensitivity may principally be the result of muscle deconditioning due to physical inactivity.

Indeed, the major finding of the present study is that, even in healthy nonobese individuals, insulin sensitivity is closely determined by muscle fat oxidative capacity. Our analysis corroborates recent literature associating insulin resistance with substantial reduction in muscle mitochondrial oxidative activity. The mechanistic explanation may imply the cytosolic accumulation of fatty acid metabolites (e.g., diacylglycerol and ceramide), which are likely to disrupt early steps in insulin signal transduction. Diacylglycerol may block upstream signaling events by promoting the serine phosphorylation of IRS-1 whereas ceramide have been shown to inhibit insulin stimulation of Akt/protein kinase B. In active individuals, the enhanced ability to oxidize intramuscular fat and fatty acid metabolites during exercise might be regarded as an important factor mediating the association between muscle fat oxidative capacity and insulin sensitivity.

The present study provides interesting observations on the association between insulin sensitivity and body fatness. Systematical studies of a large cohort of aging subjects have related the reduced insulin sensitivity to increased body fatness. In study 1, despite a doubling of fat mass and truncal fat in the elderly groups vs. young adults, insulin sensitivity was not significantly affected by age. Nevertheless, statistical analysis showed that visceral adiposity was a minor but significant determinant of insulin sensitivity. Although the implication of visceral adiposity in the etiology of the metabolic syndrome is well documented, the link between visceral adiposity and insulin sensitivity is not clearly established. On the one hand, the predominant paradigm used to explain this link is the portal/visceral hypothesis, which proposes that increased adiposity, particularly in visceral depots, leads to increased free fatty acid flux and inhibition of insulin action via Randle’s effect in insulin-sensitive tissues. On the other hand, because muscle fat oxidative capacity has been shown to play a crucial role in systemic fat balance, impaired fat oxidation in muscle might promote truncal fat accumulation. Recent data suggest that visceral adipose tissue may play a critical role as an endocrine gland, secreting numerous adipocytokines (leptin, adiponectine, TNF).

In conclusion, muscle mitochondrial function, muscle fat oxidative capacity, and insulin sensitivity were similar in young and elderly people matched for physical activity level (i.e., sedentary or endurance-trained). Muscle fat oxidative capacity was the primary determinant of insulin sensitivity; magnitude of the abdominal fat depot was a secondary predictor. Physical training induced a parallel increase in muscle fat oxidative capacity and peripheral insulin sensitivity in elderly sedentary subjects. Therefore, these results support the hypothesis that muscle ability to metabolize and oxidize fat is a major regulator of peripheral insulin sensitivity. The present study stresses the importance of physical activity in the prevention of muscle deconditioning and metabolic disorders in young and elderly populations, with particular concern for young populations that prematurely develop insulin resistance and type 2 diabetes.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1104fje; doi: 10.1096/fj.03-1104fje

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