Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
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mitochondria are responsible for improvements in blood glucose levels in diabetic subjects after that type of intervention, that study also reported a relationship between changes in SkM mitochondria and hyperglycemia as measured by HbA1c. In line with this obser- vation, Fritz et al. reported that skeletal muscle adaptations of in- creased oxidative gene expression induced by low-intensity exercise are a correlate of systemic metabolic improvements in type 2 diabetes, including insulin sensitivity ( Fritz et al., 2006 ). While causality is difficult to establish with those types of observa- tions, those studies reveal a still poorly-understood relationship between mitochondria in SkM and systemic metabolism. The aforementioned studies have collectively demonstrated that in IR mitochondria are not irreversibly impaired, and that at least partial amelioration of this abnormality can be achieved by lifestyle modifications that are typically recommended to adults with IR. However, it is also important to consider that both dietary caloric restriction and exercise are stimuli for a negative caloric balance and that while weight loss may reduce IMCL lipid content, chronic exercise increases it ( Dube et al., 2008; Goodpaster et al., 2001; Pruchnic et al., 2004 ). Therefore, it is important to consider whether weight loss and exercise training have independent ef- fects upon mitochondrial plasticity. 3.2. Separate effects of weight loss and exercise on mitochondria In normal healthy SkM, exercise training is a potent stimulus for mitochondrial biogenesis. Therefore, it stands to reason that exer- cise training may be the key factor necessary for stimulating mito- chondrial biogenesis in IR. On the other hand, the distinct possibility that mitochondrial dysfunction may be secondary to ex- cess lipid accumulation in SkM has also been proposed and thus weight loss per se might also conceivably influence mitochondrial dysfunction. In a study that compared the relative contribution of exercise training versus that of weight loss, overweight and obese subjects with insulin resistance were randomized to either diet-in- duced weight loss, or diet-induced weight loss combined with exercise training ( Toledo et al., 2008 ). Both groups experienced comparable degrees of total body weight loss, fat mass loss, and comparable improvements in SkM insulin sensitivity. However, only the group that combined training with caloric restriction experienced an improvement in mitochondrial content and respi- ratory chain enzymatic activity, demonstrating that exercise train- ing, not weight loss, is the key factor responsible for mitochondrial plasticity. Subsequent studies have confirmed that exercise train- ing can increase SkM mitochondrial content in insulin-resistant subjects with and without T2DM ( Meex et al., 2010; Phielix et al., 2010 ). Although it has now been well established that exercise train- ing per se improves mitochondrial content in IR, it is less clear whether intrinsic mitochondrial function improves too. In studies from our group, exercise training for 16–20 weeks resulted in en- hanced electron transport chain activity that exceeded changes in mitochondrial mtDNA content and citrate synthase activity, sug- gesting that training results in improvements in total oxidative capacity that exceed that expected from an increase in mitochon- drial content alone ( Toledo et al., 2007; Menshikova et al., 2005; Toledo et al., 2008 ). However, at least one study concluded that intrinsic function per mitochondrion does not improve with train- ing: subjects with T2DM and BMI-matched control individuals enrolled in a 12-week exercise program and mitochondrial func- tion was assessed by high-resolution respirometry in permeabili- zed muscle fibers ( Phielix et al., 2010 ). When mitochondrial respiratory rates were adjusted for mtDNA content, no improve- ments in mitochondrial function after exercise training were ob- served. However, compared to earlier studies ( Toledo et al., 2006; Toledo et al., 2007; Menshikova et al., 2005; Toledo et al., 2008
), this study had a relative shorter duration of training (12 weeks versus 16–20 weeks), a lower exercise training dose, and included a combination of aerobic and resistance exercise. It is likely that a certain threshold of duration of aerobic training, exercise frequency and intensity, or a combination of these, must be achieved in order to enhance intrinsic mitochondrial function, and may explain differences in the training response among stud- ies. Therefore, a conservative interpretation of the current studies published so far is that intrinsic mitochondrial function does not always improve, but may do so in certain circumstances depend- ing on the type and duration of training, and the frequency and intensity of exercise bouts. Clearly, more research is needed in this field in order to establish what the minimum exercise train- ing prescription should be in order to achieve enhancement of intrinsic mitochondrial function. The effects of weight loss in improving obesity-related insulin resistance are well established, but less is known about the impact of weight loss on SkM mitochondria. This relatively paucity of data is not surprising since mitochondrial abnormalities in obesity/IR have only been appreciated relatively recently. The majority of 32 F.G.S. Toledo, B.H. Goodpaster / Molecular and Cellular Endocrinology 379 (2013) 30–34 studies published so far show that weight loss by dietary caloric restriction does not reverse the lower mitochondrial capacity ob- served in IR, including in response to degrees of weight loss deemed clinically significant for glucose and lipid metabolism. In an older study, Kern et al. suggested an increase in succinate dehy- drogenase (SDH) activity in SkM of obese women who had under- gone moderate weight loss ( Kern et al., 1999 ). However, it is not entirely clear if the SDH activity increased in response to concom- itant changes in physical activity since the study did not control for physical activity and no objective metric of aerobic capacity was reported. Simoneau et al. studied muscle biopsy samples from ob- ese volunteers who experienced significant weight loss (14–16% of baseline weight) and observed no improvements in enzymatic markers of mitochondria, namely citrate synthase and CPT-I, sug- gesting no effect on mitochondria ( Simoneau et al., 1999 ). Cyto- chrome oxidase and beta-hydroxyacyl CoA dehydrogenase activities decreased significantly in women, but not in men, leaving some doubt about the uniformity of mitochondrial response to weight loss. We have conducted a more comprehensive assessment of the impact of weight loss per se on both mitochondrial content and function in the insulin resistant state associated with obesity ( To- ledo et al., 2008 ). Non-diabetic insulin resistant obese subjects lost 10.8% of their initial weight with moderate caloric restriction, which was associated with a nearly 30% improvement in insulin sensitivity. Subjects were instructed not to change their levels of physical activity and, accordingly, maximal aerobic capacity did not change. Despite marked weight loss and improved insulin sen- sitivity, mitochondrial content did not change as assessed by quan- titative TEM. Other markers of mitochondrial content, such as mtDNA copy number and cardiolipin content (a marker of inner- mitochondrial membrane mass), were not changed either. NADH- oxidase was also unaffected, indicating no changes in mitochon- drial function. The lack of changes in mitochondrial content and function occurred in spite of a robust decrease in IR in SkM. These observations suggest that the lower oxidative capacity in obesity/ IR cannot be explained solely as consequence of IR. This observa- tion is relevant because experimental evidence suggests that acute insulin signaling in SkM lowers mitochondrial oxidative capacity ( Asmann et al., 2006 ). Another important finding from this study was that mitochon- drial oxidative capacity did not change in spite of a reduction in IMCL content, and therefore suggests that the lower oxidative capacity in obesity/IR is unlikely to be a consequence of excess li- pid accumulation per se. Alternatively, the same result could be interpreted as an indication that perhaps greater degrees of caloric restriction are necessary for mitochondrial recovery. This does not, however, seem to the case. In a study by Berggren and colleagues, mitochondrial fatty acid oxidation was measured by incubation of skeletal muscle homogenates with [1- 14 C]palmitate and measuring 14 CO 2 production ( Berggren et al., 2008 ). Mitochondrial fatty acid oxidation in obese women who had marked weight loss (about 50 kg) was similar to that of extremely obese subjects. Moreover, SkM fatty acid oxidation did not change in extremely obese women after 1 year of weight loss (mean 55 kg lost). There were also no changes in mRNA content for PDK4, CPT I, and PGC-1a, suggesting that the transcriptional program for mitochondrial biogenesis is not activated by weight loss. Therefore, even significantly profound weight loss does not seem to result in amelioration of mitochon- drial oxidative capacity. In fact, some studies suggest that oxidative pathways may even be reduced by weight loss. After biliopancreat- ic diversion surgery for morbid obesity, weight loss reduced the expression of peroxisome proliferator-activated receptor- a (À46.7%), carnitine palmitoyltransferase-1B (À43.1%), acyl-CoA oxidase 1 (À37.8%), and acetyl-CoA carboxylase B (À48.7%) ( Fabris
et al., 2004 ). 4. Effects of weight loss and exercise on mitochondria in aging Regardless of whether or not mitochondria are mechanistically linked with IR, there is little argument that mitochondria likely play an important role in altered energy metabolism with aging. The effects of exercise to increase mitochondria content and capac- ity in older humans are also generally very consistent ( Pruchnic
et al., 2004; Jubrias et al., 2001; Menshikova et al., 2006; Orlander and Aniansson, 1980; Rimbert et al., 2004; Short et al., 2003; Waters et al., 2003 ). However, the separate effect of weight loss and exercise on mitochondria content and performance in older humans is not known. Indeed, there is some evidence to suggest that aging is associated with a blunted response to interventions known to increase mitochondria ( Reznick et al., 2007 ). A decline in mitochondria content and/or function often paral- lels the loss of muscle mass and function with age. Only until re- cently, however, have studies been conducted – in cell systems and animal models – to provide mechanistic evidence linking mitochondria with muscle growth/atrophy signaling, autophagy and sarcopenia ( Masiero et al., 2009; Romanello et al., 2010; Wenz et al., 2009 ). A conundrum for older obese men and women is that traditional diet-induced weight loss programs can result in not only loss of adipose tissue but also a significant loss of muscle ( Chomentowski et al., 2009 ). How this potentially translates into further decrements in muscle function is not clear. The CALERIE study reported that energy restriction-induced weight loss increased expression of oxidative phosphorylation genes in SkM ( Civitarese et al., 2007 ), although the related enzyme activities were unchanged. Moreover, the average age of their sub- jects was <60 years old (39–41). Subjects in the CALERIE study were not obese, and thus not representative of the typical obese insulin-resistant phenotype in which a lower mitochondrial oxida- tive capacity has been mostly reported. We have reported in a ran- domized trial that diet-induced weight loss fails to increase markers of mitochondrial oxidative capacity in overweight to ob- ese older men and women ( Dube et al., 2011 ). This was in contrast to an improvement in mitochondrial enzyme activity in those who completed an exercise-training program without significant weight loss. Although further evidence is clearly needed to deter- mine the effects of weight loss on mitochondria in the elderly, the limited evidence is consistent with that observed for middle- aged men adults. Based on the high prevalence of older adults attempting to lose weight with dieting, it is imperative to provide additional objective evidence concerning the pros and cons of weight loss in this population. 5. Conclusions In summary, the lower mitochondrial capacity associated with obesity and T2DM is not an irreversible lesion: substantial plastic- ity of mitochondrial biogenesis is retained in the insulin resistant state. However, weight loss does not appear to significantly affect this response, even when the weight loss is extreme. In contrast, increasing physical activity improves mitochondrial content and perhaps oxidative function of individual mitochondrion as well. These biological responses are not triggered by amelioration of the insulin-resistant state or a reduction in IMCL content, but likely a reflection of a concerted biological response to chronic contrac- tile activity induced by exercise. Studies of diet and exercise training have advanced our under- standing of the link between perturbations in mitochondrial oxida- tive capacity and the insulin resistant state seen in obesity, T2DM, and aging. Nevertheless, a complete picture of the role of mito- chondria in T2DM and aging remains a work in progress. More studies are necessary to establish the relative impact and F.G.S. Toledo, B.H. Goodpaster / Molecular and Cellular Endocrinology 379 (2013) 30–34 33
significance of those mitochondrial perturbations, which could lead to targeted therapies for these conditions. References Anderson, E.J., Lustig, M.E., Boyle, K.E., Woodlief, T.L., Kane, D.A., Lin, C.T., Price 3rd, J.W., Kang, L., Rabinovitch, P.S., Szeto, H.H., Houmard, J.A., Cortright, R.N., Wasserman, D.H., Neufer, P.D., 2009. Mitochondrial H 2 O
emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Invest. 119, 573–581 . Asmann, Y.W., Stump, C.S., Short, K.R., Coenen-Schimke, J.M., Guo, Z., Bigelow, M.L., Nair, K.S., 2006. Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes 55, 3309–3319 . Berggren, J.R., Boyle, K.E., Chapman, W.H., Houmard, J.A., 2008. Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise. Am. J. Physiol. Endocrinol. Metab. 294, E726–E732 . Chomentowski, P., Dube, J.J., Amati, F., Stefanovic-Racic, M., Zhu, S., Toledo, F.G.S., Goodpaster, B.H., 2009. Moderate exercise attenuates the loss of skeletal muscle mass that occurs with intentional caloric restriction-induced weight loss in older, overweight to obese adults. J. Gerontol. Ser. A – Biol. Sci. Med. Sci. 64, 575–580 . Chomentowski, P., Coen, P.M., Radikova, Z., Goodpaster, B.H., Toledo, F.G., 2011. Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J. Clin. Endocrinol. Metab. 96, 494–503 . Civitarese, A.E., Carling, S., Heilbronn, L.K., Hulver, M.H., Ukropcova, B., Deutsch, W.A., Smith, S.R., Ravussin, E., Team, C.P., 2007. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76 . Dube, J.J., Amati, F., Stefanovic-Racic, M., Toledo, F.G.S., Sauers, S.E., Goodpaster, B.H., 2008. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited. Am. J. Physiol. Endocrinol. Metab. 294, E882 . Dube, J.J., Amati, F., Toledo, F.G., Stefanovic-Racic, M., Rossi, A., Coen, P., Goodpaster, B.H., 2011. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia 54, 1147–1156 . Fabris, R., Mingrone, G., Milan, G., Manco, M., Granzotto, M., Pozza, A.D., Scarda, A., Serra, R., Greco, A.V., Federspil, G., Vettor, R., 2004. Further lowering of muscle lipid oxidative capacity in obese subjects after biliopancreatic diversion. J. Clin. Endocrinol. Metab. 89, 1753–1759 . Fritz, T., Kramer, D.K., Karlsson, H.K., Galuska, D., Engfeldt, P., Zierath, J.R., Krook, A., 2006. Low-intensity exercise increases skeletal muscle protein expression of PPARdelta and UCP3 in type 2 diabetic patients. Diabetes Metab. Res. Rev. 22, 492–498 .
and insulin resistance: evidence for a paradox in endurance-trained athletes. J. Clin. Endocrinol. Metab. 86, 5755–5761 . Hulver, M.W., Berggren, J.R., Cortright, R.N., Dudek, R.W., Thompson, R.P., Pories, W.J., MacDonald, K.G., Cline, G.W., Shulman, G.I., Dohm, G.L., Houmard, J.A., 2003. Skeletal muscle lipid metabolism with obesity. Am. J. Physiol. Endocrinol. Metab. 284, E741 . Jubrias, S.A., Esselman, P.C., Price, L.B., Cress, M.E., Conley, K.E., 2001. Large energetic adaptations of elderly muscle to resistance and endurance training. J. Appl. Physiol. 90, 1663–1670 . Kelley, D.E., Mandarino, L.J., 2000. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49, 677–683 . Kelley, D.E., Goodpaster, B., Wing, R.R., Simoneau, J.A., 1999. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am. J. Physiol. 277, E1130 . Kelley, D., He, J., Menshikova, E., Ritov, V., 2002. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes mellitus. Diabetes 51, 2944–2950 . Kern, P.A., Simsolo, R.B., Fournier, M., 1999. Effect of weight loss on muscle fiber type, fiber size capillarity, and succinate dehydrogenase activity in humans. J. Clin. Endocrinol. Metab. 84, 4185–4190 . Kim, J.Y., Hickner, R.C., Cortright, R.L., Dohm, G.L., Houmard, J.A., 2000. Lipid oxidation is reduced in obese human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 279, E1039 . Larsen, S., Nielsen, J., Hansen, C.N., Nielsen, L.B., Wibrand, F., Stride, N., Schroder, H.D., Boushel, R., Helge, J.W., Dela, F., Hey-Mogensen, M., 2012. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J. Physiol. 590, 3349–3360 . Lowell, B.B., Shulman, G.I., 2005. Mitochondrial dysfunction and type 2 diabetes. Science 307, 384–387 . Masiero, E., Agatea, L., Mammucari, C., Blaauw, B., Loro, E., Komatsu, M., Metzger, D., Reggiani, C., Schiaffino, S., Sandri, M., 2009. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507–515 . McGarry, J.D., 1995. The mitochondrial carnitine palmitoyl transerase system: its broadening role in fuel homeostasis and new insights into its molecular features. Biochem. Soc. Trans. 23, 321–324 . Meex, R.C., Schrauwen-Hinderling, V.B., Moonen-Kornips, E., Schaart, G., Mensink, M., Phielix, E., van de Weijer, T., Sels, J.P., Schrauwen, P., Hesselink, M.K., 2010. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 59, 572–579 . Menshikova, E.V., Ritov, V.B., Toledo, F.G., Ferrell, R.E., Goodpaster, B.H., Kelley, D.E., 2005. Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity. Am. J. Physiol. Endocrinol. Metab. 288, E818 . Menshikova, E.V., Ritov, V.B., Fairfull, L., Ferrell, R.E., Kelley, D.E., Goodpaster, B.H., 2006. Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J. Gerontol. Ser. A – Biol. Sci. Med. Sci. 61, 534–540 . Mootha, V.K., Lindgren, C.M., Eriksson, K.F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstrale, M., Laurila, E., Houstis, N., Daly, M.J., Patterson, N., Mesirov, J.P., Golub, T.R., Tamayo, P., Spiegelman, B., Lander, E.S., Hirschhorn, J.N., Altshuler, D., Groop, L.C., 2003. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 . Orlander, J., Aniansson, A., 1980. Effect of physical training on skeletal muscle metabolism and ultrastructure in 70 to 75-year-old men. Acta Physiol. Scand. 109, 149–154 . Patti, M.E., Butte, A.J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., Landaker, E.J., Goldfine, A.B., Mun, E., DeFronzo, R., Finlayson, J., Kahn, C.R., Mandarino, L.J., 2003. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc. Nat. Acad. Sci. USA 100, 8466–8471 . Petersen, K.F., Befroy, D., Dufour, S., Dziura, J., Ariyan, C., Rothman, D.L., DiPietro, L., Cline, G.W., Shulman, G.I., 2003. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 Download 2.44 Mb. Do'stlaringiz bilan baham: 
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