HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 89/1/453S    most recent ajcn.2008.26717Av1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Short, K. R Search for Related Content PubMed PubMed Citation Articles by Short, K. R Agricola Articles by Short, K. R

Introduction to symposium proceedings: the emerging interplay among muscle mitochondrial function, nutrition, and disease^1,2

¹ Department of Pediatrics, Section of Diabetes & Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

² Reprints not available. Address correspondence to KR Short, 1122 NE 13th Street, Suite 1400, CMRI Diabetes & Metabolic Research Program, Oklahoma City, OK 73117. E-mail: kevin-short{at}ouhsc.edu.

Mitochondria are the cellular oxidative powerhouse long recognized for their role in the conversion of fat and carbohydrate fuels into the ATP needed for cell function. Forty years ago, John Holloszy made a seminal discovery that mitochondrial size, number, and function increase in skeletal muscle in response to endurance exercise training (1). Since then, mitochondrial biogenesis has been recognized to be a key component of adaptation to exercise. Conversely, there is now a growing appreciation, which has developed within the past few years, for how reduced muscle mitochondrial content and function are common features of 3 prevalent conditions in current society: obesity, diabetes, and aging. This suggests that mitochondria may play a central role in the interaction between diet, lifestyle, and disease.

On 5 April 2008, a symposium entitled, "The Emerging Interplay among Muscle Mitochondrial function, Nutrition, and Disease" was held as part of the American Society for Nutrition's scientific program at Experimental Biology 2008 in San Diego. The purpose of the symposium was to highlight recent findings on the role of mitochondria in obesity, insulin resistance, and aging.

Lawrence Spriet provided an update on the regulation of fat oxidation in muscle and how it is influenced by obesity. Fat oxidation is reduced in obese individuals when measured at the whole-body level or in whole-cell muscle preparations. However, Spriet and his colleagues demonstrated that the reduced fat oxidation is mainly attributable to lower mitochondria content rather than a mitochondrial defect. In their studies, isolated mitochondria from lean and obese subjects oxidized fatty acids at similar rates (2). They found, however, that expression of some of the transcription factors that control mitochondria biogenesis may be regulated differentially in obesity, which may account for the lower mitochondrial protein content (3).

Kitt Petersen addressed the issue of how skeletal muscle mitochondrial function may be related to insulin resistance. Petersen et al have reported that the rate of mitochondrial oxidative phosphorylation as well as insulin sensitivity are reduced in elderly people (4). They also found that mitochondrial substrate oxidation and ATP synthesis were reduced in insulin-resistant young adults compared with age-matched people without insulin resistance (5, 6). In both of these cases, mitochondrial ATP synthesis and insulin sensitivity were inversely related to intramuscular lipid content. This led to a proposal that mitochondrial dysfunction may be closely associated with, and perhaps even precede, the development of insulin resistance. This could occur in association intracellular fat accumulation secondary to the disruption in fuel oxidation.

John Holloszy presented another perspective on the connection between insulin resistance and mitochondrial function and the role of dietary fat. Holloszy pointed out that mitochondrial fuel oxidative capacity exceeds the energy needs of skeletal muscle while at rest, during moderate intensity activity, and for insulin-mediated glucose uptake, even in subjects with obesity and insulin resistance. His group has used a high-fat diet model to show that muscle insulin resistance and mitochondrial content are not directly linked. In response to high fatty acid availability, insulin resistance to glucose uptake occurred rapidly but was followed by slower transcription factor changes that ultimately caused up-regulation of the fat oxidation pathways in mitochondria (7, 8). Thus, insulin resistance was found to coexist with mitochondrial biogenesis. This type of evidence has been used to suggest that the reduced mitochondrial content in obesity and diabetes may be secondary to insulin resistance or physical inactivity but is not responsible for insulin resistance in these conditions.

Finally, K Sreekumaran Nair summarized recent work on how mitochondrial function is affected by aging and exercise. In sedentary people, muscle content of mitochondrial gene transcripts, proteins, and DNA were shown to decrease with age (9–11); however, many of these changes appear to be closely related to lifestyle. Unlike their sedentary peers, older people who performed frequent endurance exercise training over several years showed little or no difference in mitochondrial function or biogenesis markers compared with young trained persons (9). Furthermore, when previously sedentary older people completed a standardized endurance training program, responses in muscle mitochondria were similar to those of sedentary young people who performed the same training program (11).

The main conclusion that can be drawn from this symposium is that muscle mitochondrial function, defined as the ability to perform fuel oxidation and generate ATP, is typically reduced in conditions of obesity, insulin resistance, and advanced age. Whether this represents an intrinsic dysfunction of mitochondria or a reduction in mitochondrial content may vary with specific conditions, but for the areas covered here, mitochondrial content seems to be the primary deficit. Given these findings, the next challenge should be to address ways to prevent or reverse the decline in mitochondrial function with aging, obesity, and diabetes. This brings us back to Holloszy's early finding on the power of exercise to promote mitochondrial biogenesis (1). It is increasingly clear that lifestyle changes can address many of the deficits in mitochondrial function described in this symposium. Consistent with the data presented, it has been shown that obese individuals can increase muscle fat oxidation and several mitochondrial markers in response to a regular exercise program (12–14). Similarly, endurance exercise training was shown to stimulate muscle mitochondrial biogenesis and fuel oxidative capacity changes in elderly people that are similar to responses in younger subjects (11, 14). There is even some evidence that weight loss in obese people may have beneficial effects on markers of mitochondrial biogenesis in skeletal muscle (15), although exercise or exercise plus weight loss is likely to lead to further improvements (13, 15). Collectively, these findings point to the central role mitochondria play in health and disease. [Summaries of 3 of the symposium presentations are presented in this supplement to the Journal (16–18).]

	ACKNOWLEDGMENTS

 
I thank the American Society of Nutrition (ASN) for selecting this symposium for their scientific program at Experimental Biology 2008 and both the National Dairy Council and ASN for providing travel support for the speakers.

The author has previously received travel support from the National Dairy Council and the American Society of Nutrition but has no other conflicts of interest with the material presented in this symposium.

	REFERENCES

TOP REFERENCES

 

1. Holloszy, JO. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 1967;242:2278–82..[Abstract/Free Full Text]
2. Holloway, GP, Thrush, AB, Heigenhauser, GJF, et al.. Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. Am J Physiol Endocrinol Metab 2007;292:E1782–9..[Abstract/Free Full Text]
3. Holloway, GP, Perry, CGR, Thrush, AB, et al.. PGC-1's relationship with skeletal muscle palmitate oxidation is not present with obesity despite maintained PGC-1 and PGC-1β protein. Am J Physiol Endocrinol Metab 2008;294:E1060–9..[Abstract/Free Full Text]
4. Petersen, KF, Befoy, D, Dufour, S, et al.. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300:1140–2..[Abstract/Free Full Text]
5. Petersen, KF, Dufour, S, Befroy, D, Garcia, R & Shulman, GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004;350:664–71..[Abstract/Free Full Text]
6. Befroy, DE, Petersen, KF, Dufour, S, et al.. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007;56:1376–81..[CrossRef][Medline]
7. Garcia-Roves, P, Huss, JM, Han, DH, et al.. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci USA 2007;104:10709–13..[Abstract/Free Full Text]
8. Hancock, CR, Han, D-H, Chen, M, et al.. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 2008;105:7815–20..[Abstract/Free Full Text]
9. Lanza, IR, Short, DK, Short, KR, et al.. Endurance exercise as a countermeasure for aging. Diabetes 2008;57:2933–43..[Abstract/Free Full Text]
10. Short, KR, Bigelow, ML, Kahl, J, et al.. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 2005;102:5618–23..[Abstract/Free Full Text]
11. Short, KR, Vittone, JL, Bigelow, ML, et al.. Impact of aerobic training on age-related changes in insulin action and muscle oxidative capacity. Diabetes 2003;52:1888–96..[Abstract/Free Full Text]
12. Bruce, CR, Thrush, AB, Mertz, VA, et al.. Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. Am J Physiol Endocrinol Metab 2006;291:E99–107..[Abstract/Free Full Text]
13. Berggren, JR, Boyle, KE, Chapman, WH & Houmard, JA. Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise. Am J Physiol Endocrinol Metab 2008;294:E726–32..[Abstract/Free Full Text]
14. Dube, JJ, Amati, F, Stefanovic-Racic, M, Toledo, FGS, Sauers, SE & Goodpaster, BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am J Physiol Endocrinol Metab 2008;294:E882–8..[Abstract/Free Full Text]
15. Civitarese, AE, Carling, S, Heilbronn, LK, et al.. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4:e76..[CrossRef][Medline]
16. Holloway, GP, Bonen, A & Spriet, LL. Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. Am J Clin Nutr 2009;89(suppl):455S–62S..[Abstract/Free Full Text]
17. Holloszy, JO. Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance. Am J Clin Nutr 2009;89(suppl):463S–6S..[Abstract/Free Full Text]
18. Lanza, IR & Nair, KS. Muscle mitochondrial changes with aging and exercise. Am J Clin Nutr 2009;89(suppl):467S–71S..[Abstract/Free Full Text]

This Article Full Text (PDF) All Versions of this Article: 89/1/453S    most recent ajcn.2008.26717Av1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Short, K. R Search for Related Content PubMed PubMed Citation Articles by Short, K. R Agricola Articles by Short, K. R