Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
Download 2.44 Mb. Pdf ko'rish
|
|
1896 .
exercise training effects on whole body and muscle protein metabolism. Am. J. Physiol. Endocrinol. Metab. 286, E92–101 . Short, K.R., Bigelow, M.L., Kahl, J., Singh, R., Coenen-Schimke, J., Raghavakaimal, S., Nair, K.S., 2005a. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 102, 5618–5623 . Short, K.R., Vittone, J.L., Bigelow, M.L., Proctor, D.N., Coenen-Schimke, J.M., Rys, P., Nair, K.S., 2005b. Changes in myosin heavy chain mRNA and protein expression in human skeletal muscle with age and endurance exercise training. J. Appl. Physiol. 99, 95–102 . Slivka, D.R., Dumke, C.L., Tucker, T.J., Cuddy, J.S., Ruby, B., 2012. Human mRNA response to exercise and temperature. Int. J. Sports Med. 33, 94–100 . Someya, S., Yu, W., Hallows, W.C., Xu, J., Vann, J.M., Leeuwenburgh, C., Tanokura, M., Denu, J.M., Prolla, T.A., 2010. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802– 812 .
Wernerman, J., Sahlin, K., 2003. Reduced oxidative power but unchanged antioxidative capacity in skeletal muscle from aged humans. Pflug. Arch 446, 261–269 .
Resistance training improves single muscle fiber contractile function in older women. Am. J. Physiol. Cell. Physiol. 281, C398–406 . Trappe, S., Gallagher, P., Harber, M., Carrithers, J., Fluckey, J., Trappe, T., 2003. Single muscle fibre contractile properties in young and old men and women. J. Physiol 552, 47–58 . Trappe, T., Williams, R., Carrithers, J., Raue, U., Esmarck, B., Kjaer, M., Hickner, R., 2004. Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach. J. Physiol. 554, 803–813 . Trappe, S., Hayes, E., Galpin, A.J., Kaminsky, L.A., Jemiolo, B., Fink, W.J., Trappe, T.A., Jansson, A., Gustafsson, T., Tesch, P.A., 2012. New records in aerobic power among octogenarian lifelong endurance athletes. J. Appl. Physiol. . Trounce, I., Byrne, E., Marzuki, S., 1989. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet 1, 637–639 . von Walden, F., Jakobsson, F., Edstrom, L., Nader, G.A., 2012. Altered autophagy gene expression and persistent atrophy suggest impaired remodeling in chronic hemiplegic human skeletal muscle. Muscle Nerve 46, 785–792 . Waters, D.L., Mullins, P.G., Qualls, C.R., Raj, D.S., Gasparovic, C., Baumgartner, R.N., 2009. Mitochondrial function in physically active elders with sarcopenia. Mech. Ageing Dev. 130, 315–319 . Wenz, T., 2011. Mitochondria and PGC-1alpha in aging and age-associated diseases. J. Aging Res. 2011, 810619 . Wenz, T., Rossi, S.G., Rotundo, R.L., Spiegelman, B.M., Moraes, C.T., 2009. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc. Natl. Acad. Sci. USA 106, 20405–20410 . Westphal, C.H., Dipp, M.A., Guarente, L., 2007. A therapeutic role for sirtuins in diseases of aging? Trends Biochem. Sci. 32, 555–560 . White, A.T., Schenk, S., 2012. NAD(+)/NADH and skeletal muscle mitochondrial adaptations to exercise. Am. J. Physiol. Endocrinol. Metab. 303, E308–21 . Wilkinson, S.B., Phillips, S.M., Atherton, P.J., Patel, R., Yarasheski, K.E., Tarnopolsky, M.A., Rennie, M.J., 2008. Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. J. Physiol. 586, 3701–3717 . Williamson, D.L., Raue, U., Slivka, D.R., Trappe, S., 2010. Resistance exercise, skeletal muscle FOXO3A, and 85-year-old women. J. Gerontol. A Biol. Sci. Med. Sci. 65, 335–343
. Wright, D.C., Han, D.H., Garcia-Roves, P.M., Geiger, P.C., Jones, T.E., Holloszy, J.O., 2007. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J. Biol. Chem. 282, 194–199 . Zhang, C., Cuervo, A.M., 2008. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959–965
. Zucchini, C., Pugnaloni, A., Pallotti, F., Solmi, R., Crimi, M., Castaldini, C., Biagini, G., Lenaz, G., 1995. Human skeletal muscle mitochondria in aging: lack of detectable morphological and enzymic defects. Biochem. Mol. Biol. Int. 37, 607–616 .
muscle myosin heavy chain genes. Focus on ‘‘Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading’’. Am. J. Physiol. Cell Physiol. 297, C1–3 . A.R. Konopka, K. Sreekumaran Nair / Molecular and Cellular Endocrinology 379 (2013) 19–29 29 The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging Frederico G.S. Toledo, Bret H. Goodpaster ⇑ Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States a r t i c l e i n f o Article history: Available online 20 June 2013 Keywords: Mitochondria Weight loss Exercise Physical activity Skeletal muscle Obesity
a b s t r a c t Mitochondria within skeletal muscle have been implicated in insulin resistance of obesity and type 2 dia- betes mellitus as well as impaired muscle function with normal aging. Evaluating the potential of inter- ventions to improve mitochondria is clearly relevant to the prevention or treatment of metabolic diseases and age-related dysfunction. This review provides an overview and critical evaluation of the effects of weight loss and exercise interventions on skeletal muscle mitochondria, along with implications for insu- lin resistance, obesity, type 2 diabetes and aging. The available literature strongly suggests that the lower mitochondrial capacity associated with obesity, type 2 diabetes and aging is not an irreversible lesion. However, weight loss does not appear to affect this response, even when the weight loss is extreme. In contrast, increasing physical activity improves mitochondrial content and perhaps the function of indi- vidual mitochondrion. Despite the consistent effect of exercise to improve mitochondrial capacity, stud- ies mechanistically linking mitochondria to insulin resistance, reductions in intramyocellular lipid or improvement in muscle function remain inconclusive. In summary, studies of diet and exercise training have advanced our understanding of the link between mitochondrial oxidative capacity and insulin resis- tance in obesity, type 2 diabetes and aging. Nevertheless, additional inquiry is necessary to establish the significance and clinical relevance of those perturbations, which could lead to targeted therapies for a myriad of conditions and diseases involving mitochondria. Ó 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Mitochondria within skeletal muscle (SkM) provide energy re- quired for contraction, and by extension, mobility and the ability to perform physical work. To support this primary role of skeletal muscle, mitochondria are also critical to other essential myocellu- lar functions, including storage and utilization of fuel, primarily glucose and fatty acids, as well as cell signaling and modulating oxidative stress. Therefore, it is not surprising that mitochondria within skeletal muscle have been implicated in aging as well as insulin resistance (IR) of obesity and type 2 diabetes mellitus (T2DM). Targeting mitochondria with interventions to prevent, attenuate, or treat aging, age-related diseases and metabolic dis- eases and dysfunction could then have important public health implications. The primary purpose of this review is to provide an objective overview and critical evaluation of studies examining the effects of weight loss and exercise interventions on skeletal muscle mitochondria, along with implications for deranged energy metabolism, most notably IR, obesity, T2DM and aging. 2. A potential role for mitochondria in the pathophysiology of skeletal muscle insulin resistance Despite a great deal of progress that has been made in unravel- ing the mechanisms behind the etiology of IR, its pathophysiology remains far from clear. This is due in part to the recognized multi- plicity of factors that contribute to the development of IR. No single disturbance exclusively explains the pathophysiology of this con- dition. For instance, both genetic and a number of acquired factors (e.g., obesity, sedentary lifestyle, and neurohormonal influences) work in concert to modulate insulin sensitivity in organs such as liver and muscle, which are responsible for partitioning glucose and maintaining normal plasma glucose homeostasis. Therefore, several players participate in the pathophysiology of IR. In the past decade, mitochondria have emerged as an additional player in IR associated with obesity, T2DM, and perhaps aging. Although mitochondria have been reported as abnormal or ‘‘dysfunctional’’ in insulin-resistant states and aging, their exact role in glucose homeostasis and fuel metabolism is not completely understood. Nevertheless, in the context of IR of obesity, T2DM and aging, there have been great advances in our understanding of how mitochondria react to weight loss and to physical activity. These 0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.06.018 ⇑ Corresponding author. Address: University of Pittsburgh, 3459 Fifth Avenue, MUH N810, Pittsburgh, PA 15213, United States. Tel.: +1 412 692 2848; fax: +1 412 692 2165. E-mail address: bgood@pitt.edu (B.H. Goodpaster). Molecular and Cellular Endocrinology 379 (2013) 30–34 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e advances have shed light on the relationship between mitochon- dria and fuel metabolism. The objective of this review is to give the reader an overview of what has been learned from human studies that have investigated how skeletal muscle mitochondria adapt and react to changes in metabolism induced by diet and exercise in the context of glucose metabolism. This review will focus predominantly on human SkM studies for two reasons: (a) Reports of abnormal mitochondrial capacity in SkM have direct relevance to human disease; and (b) While the association between mitochondria and obesity-induced IR has been replicated numerous times in humans, animal data has been less consistent and probably reflective of interspecies dif- ferences between animals and humans. 2.1. Terminology Terms such as ‘‘mitochondrial dysfunction’’ ( Petersen et al., 2003; Petersen et al., 2004 ) and ‘‘mitochondrial impairments’’ ( Kel- ley et al., 2002 ) have been commonly employed in the obesity, dia- betes, and physiology of aging literature. However, this review favors avoiding those terminologies, because they are potentially confusing for a couple of reasons. First, ‘‘dysfunction’’ implies pathology in SkM, but it is far from established whether altered mitochondria reflect a physiological adaptation, pathological mal- adaptation, or primarily a pathological phenomenon. Second, there is a multiplicity of mitochondrial functions in cell biology. Mito- chondrial function can be measured in terms of ATP generation, substrate oxidation, intracellular calcium buffering, induction of apoptosis, to name a few. Therefore, the term mitochondrial ‘‘func- tion’’ can be imprecise unless clearly defined. In this review, mito- chondrial function specifically refers to the function of fuel oxidation. Furthermore and equally important, the total mitochon- drial oxidative capacity of a cell depends on not only its total mito- chondrial content, but also on the functional capacity of each mitochondrion (i.e. ‘‘intrinsic mitochondrial function’’). When referring to mitochondrial ‘‘function’’ or ‘‘dysfunction’’, it may not be always obvious whether it refers to either a deficit in total oxi- dative capacity, or to the intrinsic function of each mitochondrion. Since the total oxidative capacity of a cell depends on both content and function of mitochondria, we prefer to employ the term mito- chondrial capacity , as adopted in previous studies ( Toledo et al., 2006; Toledo et al., 2007; Toledo et al., 2008 ), to denote the global integrated components of content and function, which is a more relevant parameter for cell metabolism. Thus, whenever appropri- ate, mitochondrial function per individual mitochondrion or mito- chondrial content will be specified. It should also be noted that the term ‘mitochondrial capacity’ reflects the maximal cellular capacity for oxidation in SkM. Therefore, the term distinctively does not ap- ply to situations where measurements occur in sub-maximal con- ditions of metabolic demand (e.g. muscle at rest); in those instances mitochondrial activity for a given condition, rather than maximal capacity, is being quantified. 2.2. Are mitochondria abnormal in insulin-resistant skeletal muscle? At a cellular level, a common feature of IR is the presence of in- creased lipid accumulation in insulin-responsive tissues such as li- ver and SkM. This ectopic fat accumulation helps explain why obesity and lipodystrophy are associated with IR: when adipose tissue capacity to store lipids is sub-optimal, lipid is ectopically stored in SkM and liver, but this ectopic fat disrupts substrate uti- lization in these tissues, leading to IR. While excess intramyocellu- lar lipid (IMCL) has been clearly associated with IR, and excess lipid supply to muscle certainly plays a role in conditions of energy ex- cess, high-fat diet and obesity, the underlying cellular mechanisms for inappropriate accumulation of lipids during physiological con- ditions are much less clear. Since lipids are oxidized in mitochon- dria, one such factor could theoretically be the overall mitochondrial capacity of SkM. It has been theorized that if defi- cient, a reduced mitochondrial capacity might predispose to lipid accumulation and thus aggravate IR ( Lowell and Shulman, 2005 ). Since the pioneering studies by Randle and colleagues in the 1960s ( Randle et al., 1963 ) supporting a model of fuel competition and IR, there have been numerous investigations into the role of fuel selection in the etiology of muscle IR (for a review see Kelley
and Mandarino, 2000 ). Many of these earlier studies revealed impairments in fatty acid oxidation, lower mitochondrial enzyme activities and lower expression of genes related to oxidative capac- ity within skeletal muscle in obesity and T2DM ( Hulver et al., 2003; Kelley et al., 1999; Kim et al., 2000; McGarry, 1995; Simoneau et al., 1999; Mootha et al., 2003; Patti et al., 2003 ). 3. Effects of weight loss and exercise training on mitochondrial oxidative capacity in insulin-resistant obesity While a lower mitochondrial oxidative capacity observed in insulin-resistant subjects has been consistently demonstrated, its pathophysiological significance remains unsettled. To date, it is not clear whether it represents a pathological defect or a physio- logical adaptation. Favoring the notion that it represents a patho- logical state, the term ‘‘mitochondrial dysfunction’’ has been proposed ( Petersen et al., 2003; Kelley et al., 2002 ). In support of this hypothesis, signs of mitochondrial abnormalities were re- ported in lean healthy subjects with a parental history of type 2 diabetes, raising the possibility of an inheritable etiology ( Petersen
et al., 2004 ). However, others have proposed that the lower oxida- tive capacity in IR is not necessarily a form of mitochondrial pathology and may represent a consequence of the insulin-resis- tant state or stress induced by nutrient overload ( Stump et al., 2003; Anderson et al., 2009 ). While it remains unclear whether the reduction in oxidative capacity represents either a defect or an adaptation, the extent to which it is either reversible or an enduring defect has now been well characterized by interventional studies that are discussed in this review. Examining how mito- chondria respond to weight loss, exercise training, and insulin sen- sitizers has broadened our understanding of mitochondrial biology in IR. One of the earliest studies to suggest that significant mitochon- drial plasticity is preserved in the obese/insulin-resistant state showed that overall oxidative capacity in SkM can be improved by lifestyle modifications typically recommended for obesity ( Menshikova et al., 2005 ). In a 16-week lifestyle modification pro- gram consisting of reduced calorie intake and weekly moderate- intensity aerobic training, obese non-diabetic volunteers experi- enced a 9.7% weight loss and significant improvements in whole- body aerobic capacity, insulin sensitivity and whole-body fat oxi- dation. In parallel with these changes, total NADH oxidase and suc- cinate oxidase activities were increased after the intervention, denoting improved electron-transport chain oxidative capacity and remodeling of mitochondrial oxidative capacity. However, mtDNA content was not significantly increased in response to the intervention, suggesting impaired biogenesis with intact functional remodeling of mitochondria. In line with the notion of subnormal biogenesis, citrate synthase (a surrogate marker of mitochondrial content) was unchanged in half of the participants in that study. Similarly, citrate synthase was also unchanged in the CALERIE study, in which overweight volunteers underwent either caloric restriction or caloric restriction with exercise. In both instances, citrate synthase activity did not increase ( Civitarese et al., 2007 ). The uncertainty surrounding the effect of those interventions on mitochondrial content expansion may be in part attributable F.G.S. Toledo, B.H. Goodpaster / Molecular and Cellular Endocrinology 379 (2013) 30–34 31
to methodological reasons. The tight cytoskeleton apparatus of SkM represents a technical challenge for isolation of mitochondria and pure mitochondrial preparations without contaminants are not easy to obtain. Furthermore, mitochondria can be functionally harmed during isolation methods resulting in potentially mislead- ing results ( Picard et al., 2010; Picard et al., 2011 ), For instance, mtDNA has been shown to be a poor marker of mitochondrial con- tent (
Larsen et al., 2012 ). Finally, at least in some instances citrate synthase can be regulated by exercise in a manner disconnected to mitochondrial content ( Tonkonogi et al., 1997 ). The first unequiv- ocal demonstration that mitochondrial content expands in re- sponse to lifestyle modifications in obesity/IR was made possible by studies employing transmission electron microscopy with quantitative stereologic analysis ( Toledo et al., 2006 ). The advan- tage of that approach is that mitochondrial content is measured in situ
, therefore overcoming the issues of preparation purity, func- tional damage, and modulation of enzyme activity independent of enzyme content. Using that approach, it was found that SkM mito- chondrial content increased on average by 42% after weight loss and exercise training ( Toledo et al., 2006 ). Mitochondrial morphol- ogy was also affected, noted by a 19% increase in mitochondrial size. In that study, both mitochondrial content and size strongly correlated with the degree of change in insulin sensitivity (r = 0.72 and r = 0.68, respectively). While not necessarily suggest- ing causality, it reinforced the notion of a tight link between mito- chondria and IR. However, as will be discussed later in this review, the link between mitochondria and insulin resistance can some- times be dissociated. 3.1. Intervention effects in T2DM In the spectrum of obesity and IR, the most severe impairments in mitochondrial content seem to occur in T2DM ( Chomentowski et al., 2011 ). Subjects with T2DM also display the greatest degrees of derangements in insulin sensitivity in SkM and the greatest IMCL lipid accumulation. They also have hyperglycemia, which might conceivably be another insult to mitochondria. But as dem- onstrated by interventional studies, even subjects with T2DM re- tain a substantial capacity for increasing mitochondrial biogenesis in response to simple lifestyle modifications. In a study involving subjects with T2DM, a 4-month intervention consisting of diet to achieve weight loss and daily exercise training resulted in robust improvements in SkM mitochondrial oxidative capacity ( Toledo et al., 2007 ). Mitochondrial content measured by quantita- tive TEM, citrate synthase, and the activity of NADH oxidase were all increased by the intervention. While many factors unrelated to Download 2.44 Mb. Do'stlaringiz bilan baham: 
|