Skeletal muscle ‘‘mitochondrial deficiency’’ does not mediate insulin resistance1–3

John O Holloszy
ABSTRACT Patients with type 2 diabetes, insulin-resistant obese individuals, and insulin-resistant offspring of patients with diabetes have ’30% less mitochondria in their skeletal muscles than age-matched healthy controls. It has been hypothesized that this ‘‘deficiency’’ of mitochondria mediates insulin resistance by impairing the ability of muscle to oxidize fatty acids (FAs). However, a 30% decrease in mitochondria should not impair the ability of muscle to oxidize FAs because the capacity of muscle to oxidize substrate is far in excess of what is needed to supply energy in the basal state, ie, in resting muscle. In pathologic states in which mitochondrial content/ function is so severely impaired as to limit substrate oxidation in resting muscle, glucose uptake and insulin action are actually enhanced. Recent studies have shown that feeding rodents high-fat diets and raising FA concentrations results in muscle insulin resistance despite an increase muscle mitochondria that enhances the capacity for fat oxidation. Furthermore, it was recently shown that skeletal muscle mitochondrial capacity for oxidative phosphorylation in Asian Indians with type 2 diabetes is the same as in nondiabetic Indians and higher than in healthy European Americans. In light of this evidence, it seems highly unlikely that ‘‘mitochondrial deficiency’’ causes muscle insulin resistance. Am J Clin Nutr 2009;89(suppl):463S–6S.

’30% less mitochondria than normal was confirmed and extended to obese insulin-resistant individuals and to insulinresistant offspring of diabetic parents in subsequent studies (3–9). As a result of these findings, the concept that mitochondrial deficiency/dysfunction causes muscle insulin resistance appears to have been widely accepted (10–12). The mechanism that has been proposed to mediate the insulin resistance is a decrease in the capacity to oxidize fat, resulting in accumulation of intramuscular lipids (2, 10, 11). In support of this concept, it has been reported that both substrate oxidation, determined noninvasively by using [13C]magnetic resonance spectroscopy to measure incorporation 13C from [13C]acetate into glutamate, and the rate of mitochondrial oxidative phosphorylation is 30% lower in resting muscle of insulin-resistant individuals than in normal individuals (6, 13). In keeping with the concept that mitochondrial deficiency causes insulin resistance, it has also been reported that feeding rodents high-fat diets of the type that result in muscle insulin resistance results in decreases in muscle peroxisome proliferator activated receptor c coactivator 1a (PGC1a) mRNA (14–16) and protein (14) concentrations, as well as in the levels of a range of mitochondrial enzymes (14).

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The incidence of obesity, metabolic syndrome, and type 2 diabetes has attained epidemic proportions and is, arguably, our most serious current public health problem. Because insulin resistance is the primary cause of type 2 diabetes, the mechanism responsible for decreased insulin action in prediabetes and type 2 diabetes has been the subject of intense investigation. One line of research on this topic has led to the hypothesis that a deficiency and/or dysfunction of muscle mitochondria is responsible for the insulin resistance that leads to type 2 diabetes. The purpose of this review is to marshal the evidence against this concept.

The rate of substrate oxidation in muscle is regulated by the rate of ATP breakdown/ADP production, which is determined by the cells’ energy requirement (17). In resting muscle cells, the demand for energy/ATP is determined by housekeeping functions, such as protein synthesis and maintenance of membrane potential, and is very low relative to the maximal capacity of muscle to oxidize substrate. Increasing the supply of FAs or glucose to resting muscle does not increase the rate of substrate oxidation above what is needed for ATP resynthesis, although it can change the relative proportions of these substrates that are oxidized.

Kelley and coworkers (1, 2) found that the muscles of patients with type 2 diabetes contain less mitochondria than those of age-matched insulin-sensitive individuals. They hypothesized that this reduction in mitochondrial content impairs the ability of muscle to oxidize fatty acids (FAs), and that this results in intramuscular lipid accumulation and insulin resistance (1, 2). The finding that muscles of patients with type 2 diabetes contain

From the Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO. 2 Presented at the symposium ‘‘The Emerging Interplay among Muscle Mitochondrial Function, Nutrition, and Disease,’’ held at Experimental Biology 2008, San Diego, CA, 5 April 2008. 3 Reprints not available. Address correspondence to JO Holloszy, Washington University School of Medicine, 4566 Scott Avenue, Campus Box 8113, St Louis, MO 63110. E-mail: First published online December 3, 2008; doi: 10.3945/ajcn.2008.26717C.

Am J Clin Nutr 2009;89(suppl):463S–6S. Printed in USA. Ó 2009 American Society for Nutrition




Skeletal muscle contains sufficient mitochondria to make possible a ’150-fold increase in oxygen uptake per kilogram of muscle during strenuous exercise in well-trained young individuals (18). Middle-aged patients with type 2 diabetes are usually in poor physical condition with a low maximal oxygen uptake capacity (4). However, even if one makes the very conservative assumption that the maximal oxygen uptake capacity of the muscles of insulin-resistant patients is only 25% as great as that of young trained men, this still represents a 30–40-fold increase above resting values. Because the capacity of muscle to oxidize substrate is so far in excess of what is needed to supply the energy needs of resting muscle, it seems clear that a ’30% decrease in mitochondrial content should have no effect on the ability of resting muscle to oxidize fat. If oxygen uptake/substrate oxidation is measured under state 3 conditions, ie, when the availability of ADP, inorganic phosphate (Pi), and substrate is not limiting, in permeabilized muscle fibers, muscle homogenates, or the mitochondrial fraction of muscle, one would expect to find a 30% lower value in diabetic than in control muscle. In other words, maximal oxidative capacity should be decreased in proportion to the lower content of mitochondria. This expected relation is what was found by Boushel et al (9) in muscle from patients with type 2 diabetes, and by Holloway et al (19) in muscle from obese women, compared with normal controls. These investigators evaluated whether there is mitochondrial dysfunction in insulin-resistant muscle and found that, although there was a decrease in mitochondrial content, the remaining mitochondria functioned normally (9, 19). It has also been reported that the increase in oxidative phosphorylation in muscle in response to insulin is lower in muscle from patients with diabetes than in normal muscle (20). The increase in ATP turnover in response to insulin is mediated by the increase in the rate of ADP production that results from increased glucose uptake and ATP utilization in the reactions catalyzed by hexokinase and nucleoside diphosphate kinase, ie, 2 ATPs for each glucose molecule taken up. The smaller increase in oxidative phosphorylation in diabetic muscle in response to insulin is the result of a lower rate of glucose transport into the insulinresistant muscles. On the other hand, the rates of substrate oxidation and oxidative phosphorylation in muscles not stimulated by insulin or exercise are determined by the low rate of ATP utilization/ADP production required for housekeeping functions, not by mitochondrial content, except when a pathologic process has destroyed or damaged most of the mitochondria. In the above context, the reports (6, 13) that substrate oxidation and ATP production rates in muscle are 30% lower in insulinresistant individuals than in normal individuals under basal conditions are puzzling. For such a decrease in resting oxidative metabolism to occur, the energy requirement for ‘‘housekeeping’’ functions would have to be 30% lower than normal in insulinresistant muscle. Alternatively, if mitochondria are more tightly coupled in insulin-resistant muscle, so that more ATP is formed per oxygen molecule, this could explain a lower rate of substrate oxidation but not a slower rate of ATP formation. If the ability of muscle to oxidize fat in the basal state is not impaired in insulin-resistant individuals, what is the explanation for the well-documented elevation of their intramyocellular lipid (IMCL) content? Clearly, impaired oxidative capacity is not the only mechanism for an increase in IMCL lipid stores, as evi-

denced by the finding that highly trained athletes also frequently have high IMCL despite an increase in muscle mitochondria (21–23). The likely cause is increased delivery and/or uptake of FAs in excess of the muscle cells’ energy requirement.

Although insulin-resistant individuals usually have ’30% less mitochondria in their muscles than average, their capacity for aerobic metabolism is still within the normal range (4). Unless they have some additional pathology, patients with type 2 diabetes and insulin-resistant offspring of diabetic parents are not limited in their everyday physical activities. In contrast, a decrease in muscle mitochondrial number, or a mitochondrial pathology/dysfunction sufficiently severe to limit the rate of ATP production at rest, will result in such extreme muscle fatigue and weakness that normal physical activity becomes impossible. Contrary to the ‘‘mitochondrial deficiency causes insulin resistance’’ hypothesis, a number of studies have shown that in pathologic states in which mitochondrial deficiency is so severe that it limits the rate of substrate oxidation in resting muscle, both basal and insulin-stimulated glucose transport are increased (24, 25) despite a large accumulation of IMCL (24). Hypoxia, which represents the ultimate degree of mitochondrial dysfunction or nonfunction, also increases basal and insulinstimulated glucose transport (26, 27). These responses to extreme mitochondrial dysfunction are mediated by a decrease in the ATP:AMP ratio with activation of AMP-dependent protein kinase (24, 25, 27), which stimulates glucose transport, increases muscle insulin sensitivity, and induces increased expression of the GLUT4 glucose transporter (27, 28). Rodents fed high-fat diets develop muscle insulin resistance within a few weeks. If the high-fat diet is continued long enough, the insulin resistance progresses to the rodent equivalent of metabolic syndrome or type 2 diabetes, depending on the genetic background (29–32). The recent finding that, in rats fed high-fat diets, muscle insulin resistance develops concomitantly with an increase in muscle mitochondria and oxidative capacity provides direct evidence against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria (33, 34). A recent study showing that skeletal muscle mitochondrial capacity for oxidative phosphorylation in insulin-resistant Asian Indians with type 2 diabetes is the same as in nondiabetic Indians and higher than in healthy Americans of northern European descent also demonstrates that insulin resistance is not due to mitochondrial deficiency (35).

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It has been reported that raising FA levels in humans (14) and feeding rodents high-fat diets (14–16) cause a decrease in PGC1 mRNA in muscle. In a study by Sparks et al (14), feeding mice a high-fat diet for 3 weeks was reported to result in ’90% decreases in the mRNA levels of PGC1a and a number of mitochondrial enzymes, and ’40% decreases in the protein levels of PGC1a and cytochrome c. On the other hand, earlier studies showed that high-fat diets induce increases in mitochondrial enzymes (36–39). Other, more recent studies have shown that



raising serum FAs to very high levels with a high-fat diet plus heparin (40), or a more modest increase in FA induced by a highfat diet alone (33, 34), induces an increase in mitochondrial biogenesis as evidenced by increases in the protein levels of a range of mitochondrial enzymes, in the capacity to oxidize FAs, and in mitochondrial DNA copy number. Additional evidence that FAs stimulate mitochondrial biogenesis comes from a study showing that overexpression of lipoprotein lipase in muscle results in a large increase in mitochondria (41) and from the observation that lowering serum free FA with the use of acipimox results in a decrease in expression of a number of mitochondrial markers (42). The FA-induced increase in mitochondrial biogenesis is mediated by an increase in PGC1a protein (33, 34, 43) that occurs in the absence of an increase in PGC1a mRNA (34, 40). In contrast to the transcriptionally mediated increases in PGC1a expression induced by stimuli such as exercise (44–47), calcium (48), and cold (49), which occur rapidly (within hours), the posttranscriptionally mediated increase in PGC1a induced by an increase in FAs occurs very slowly (’4 wk) (34). Previous studies documented that activation or overexpression of peroxisome proliferator activated receptor d (PPARd) in skeletal muscle induces an increase in mitochondrial biogenesis (50, 51). The authors concluded that this effect was mediated directly by PPARd, because increasing PPARd activity or expression did not result in an increase in PGC1a mRNA, and PGC1a protein was not measured (50, 51). FAs are natural ligands/activators of PPARd (52), and raising serum FAs results in activation of PPARd (40). Therefore, it is probable that activation of PPARd is the initial step in the pathway by which raising FA concentrations causes an increase in mitochondrial biogenesis. However, PPARd regulates the expression of only a subset of mitochondrial proteins. An increase in mitochondrial biogenesis requires the coordinated expression of a large number of genes encoded in the nucleus, as well as the genes encoded in the mitochondrial genome. This process requires the activation of various transcription factors, including nuclear respiratory factor 1 (NRF-1), NRF-2, mitochondrial transcription factor A (TFAM), estrogen-related receptors (ERRs), and myocyte enhancer factors (MEFs) (53–55) in addition to PPARd. The transcription coactivator PGC1a, which activates the NRFs, ERRs, PPARs, and MEFs, mediates the coordinated increase in transcription of the genes encoding mitochondrial proteins (54, 55). The interpretation that FAs induce an increase in mitochondrial biogenesis by inducing a posttranscriptional increase in PGC1a is supported by the finding that overexpression of PPARd in skeletal muscle induces an increase in PGC1a expression in the absence of an increase in PGC1a mRNA (34). The mechanism by which PPARd increases PGC1 protein expression is still unknown. If the decrease in muscle mitochondria associated with insulin resistance and its consequences is not mediated by FAs, what is responsible? One possibility raised by Asmann and coworkers (8) is that ‘‘muscle mitochondrial dysfunction in type 2 diabetes is not an intrinsic defect but instead a functional defect related to impaired response to insulin.’’ Support for this possibility is provided by a study on mice that developed insulin resistance and diabetes in response to a high-fat, high-sucrose diet (56). In that study, insulin resistance developed within 1 mo on the diet, whereas mitochondria remained normal. However, an extended

diet intervention that induced diabetes resulted in decreased mitochondrial biogenesis, structure, and function, which the authors attributed to oxidative stress. Further support is provided by a study reporting that rosiglitazone administration in patients with type 2 diabetes restored muscle PGC1a and PPARd gene expression and succinate dehydrogenase activity to normal levels (57). A second possibility, that the susceptibility to development of type 2 diabetes and low muscle content of mitochondria are genetically linked, is suggested by the finding that insulinresistant offspring of parents with type 2 diabetes have or show a ’30% reduction in muscle mitochondria before developing hyperglycemia or other metabolic abnormalities (other than insulin resistance) (6, 7). A third possibility is that exercise deficiency is the cause of the mitochondrial deficiency, because obesity, insulin resistance, and type 2 diabetes are to a large extent the result of exercise deficiency in genetically predisposed individuals whose energy intake is not balanced by energy expenditure. In support of this possibility, exercise training has been shown to normalize muscle mitochondrial content in patients with type 2 diabetes (58). In conclusion, although the mechanism responsible for the finding that insulin-resistant individuals have ’30% less mitochondria in their muscles than normal individuals has not yet been determined, it seems clear from the information reviewed above that this mitochondrial deficiency is not responsible for muscle insulin resistance. (Other articles in this supplement to the Journal include references 59 and 60.)
The author had no conflicts of interest.

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