Elsevier

Metabolism

Volume 59, Issue 7, July 2010, Pages 967-976
Metabolism

α-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate–activated protein kinase–peroxisome proliferator-activated receptor-γ coactivator-1α signaling in the skeletal muscle of aged mice

https://doi.org/10.1016/j.metabol.2009.10.018Get rights and content

Abstract

Skeletal muscle mitochondrial dysfunction is associated with aging and diabetes, which decreases respiratory capacity and increases reactive oxygen species. Lipoic acid (LA) possesses antioxidative and antidiabetic properties. Metabolic action of LA is mediated by activation of adenosine monophosphate–activated protein kinase (AMPK), a cellular energy sensor that can regulate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. We hypothesized that LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK–PGC-1α signaling in the skeletal muscle of aged mice. C57BL/6 mice (24 months old, male) were supplemented with or without α-LA (0.75% in drinking water) for 1 month. In addition, metabolic action and cellular signaling of LA were studied in cultured mouse myoblastoma C2C12 cells. Lipoic acid supplementation improved body composition, glucose tolerance, and energy expenditure in the aged mice. Lipoic acid increased skeletal muscle mitochondrial biogenesis with increased phosphorylation of AMPK and messenger RNA expression of PGC-1α and glucose transporter–4. Besides body fat mass, LA decreased lean mass and attenuated phosphorylation of mammalian target of rapamycin (mTOR) signaling in the skeletal muscle. In cultured C2C12 cells, LA increased glucose uptake and palmitate β-oxidation, but decreased protein synthesis, which was associated with increased phosphorylation of AMPK and expression of PGC-1α and glucose transporter–4, and attenuated phosphorylation of mTOR and p70S6 kinase. We conclude that LA improves skeletal muscle energy metabolism in the aged mouse possibly through enhancing AMPK–PGC-1α–mediated mitochondrial biogenesis and function. Moreover, LA increases lean mass loss possibly by suppressing protein synthesis in the skeletal muscle by down-regulating the mTOR signaling pathway. Thus, LA may be a promising supplement for treatment of obesity and/or insulin resistance in older patients.

Introduction

Obesity and related metabolic syndrome continue to be a major public health problem in the developed world. Both obesity and insulin resistance increase with aging, which is associated with reduced mitochondrial mass and function, leading to a defective energy homeostasis [1], [2], [3]. A substantial decline in mitochondrial oxidative capacity in the skeletal muscle may contribute to the whole-body aging process [1]. A reduction in respiration rate and mitochondria biogenesis accounts for a defective energy expenditure, which predisposes to obesity, type 2 diabetes mellitus, and other metabolic consequences [4]. Energy metabolism in the skeletal muscle is finely regulated in healthy subjects; however, such regulation may be impaired in aging and diabetes [5]. The mechanisms that regulate body composition and energy homeostasis are not fully understood.

Nutrient supplementation has been applied to slow down the aging process and improve the quality of life. Supplemented lipoic acid (LA) [1], an essential cofactor in mitochondrial dehydrogenase complexes, might protect against aging-related mitochondrial dysfunction [6], [7] and increases glucose utilization in type 2 diabetes mellitus in vivo [8], [9]. Recently, LA has been shown to induce body weight (BW) loss by inhibiting hypothalamic adenosine monophosphate–activated protein kinase (AMPK) activity, resulting from suppressed food intake and stimulated energy expenditure [10]. In addition, LA treatment combined with acetylcarnitine increases ambulatory activity in aged rats [11] and improves mitochondrial function with attenuated oxidative damage [12]. Skeletal muscle is a key tissue and a major contributor to whole-body energy homeostasis in humans [13]. However, it is unknown whether LA supplementation increases mitochondrial biogenesis and energy metabolism in skeletal muscle of aged mice.

Adenosine monophosphate–activated protein kinase is a highly conserved cellular energy sensor. It appears as an intracellular fuel gauge that is activated by a drop in the adenosine triphosphate to AMP ratio [14]. One mechanism by which activated AMPK stimulates glucose uptake, fatty acid oxidation, and mitochondrial biogenesis in skeletal muscle is by increasing glucose transporter–4 (GLUT-4) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression [15], [16], [17]. Furthermore, metformin treatment in type 2 diabetes mellitus activates AMPK, leading to enhanced glucose disposal in skeletal muscle [18]. Interestingly, the increase in AMPK activity results in suppressed skeletal muscle protein synthesis. Lipoic acid has been reported to increase AMPK activity in skeletal muscles in diabetes-prone obese rats and in C2C12 myotubes, which is accompanied by improved glucose metabolism and fatty acid oxidation [19], [20]. Previous studies focused on LA-mediated antioxidative protective effects in aged mice [21], [22], although its metabolic effects in energy metabolism are also evident in obese and/or diabetic mice [19], [23]. Considering LA-mediated activation of AMPK, however, it is not known whether LA supplementation facilitates mitochondrial biogenesis and/or inhibits protein loss in aged mice. Therefore, we hypothesized that α-LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK–PGC-1α signaling in the skeletal muscle of aged mice. Our objectives in the present study are to determine whether LA-stimulated energy expenditure and protein loss are mediated by activating the AMPK–PGC-1α signaling pathway in the skeletal muscle of aged mice.

Section snippets

Experiment procedures

All experiments were approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine. The C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were fed ad libitum (standard rodent diet 2920; Harlan Teklad, Madison, WI) and given free access to water for 24 months. Individual male mice (at the age of 24 months) were provided with water supplemented with 0% (n = 10, as control group) or 0.75% α-LA (Sigma-Aldrich, St Louis, MO; n = 10, as treatment group) for 1 month. Body

Food intake and body composition

Daily intake of food was decreased (P < .05) by 18% in LA-treated mice (4.50 ± 0.30 g/d) compared with that (5.50± 0.30 g/d) in control mice. Over the period of 4 weeks, LA-treated mice lost (P < .05) BW of 5.27 ± 0.62 g (an equivalent of 15.8% of initial BW), whereas the control mice maintained their BW. The LA-treated mice had less adipose as well as lean mass (Fig. 1A). Therefore, the LA-treated mice had lower percentage of fat mass (Fig. 1B), but higher percentage of lean and bone mass.

Energy expenditure

The

Discussion

In the present study, we demonstrated that oral intake of α-LA improved body composition, glucose tolerance, and energy expenditure of the aged mice, which was associated with increased mitochondrial biogenesis in the skeletal muscle. It is well known that the aging in humans is associated with increased fat mass, declined lean mass [19], [27], and decreased basal metabolic rate [28]. Previous studies have demonstrated that dietary LA increases whole-body energy expenditure in adult mice [10];

Acknowledgment

The authors thank Qiang Tong, Douglas Burrin, Nancy Butte, and Adam Gillum at Baylor College of Medicine for scientific and technical support. This work is supported by the US Department of Agriculture (USDA)/Agricultural Research Service under Cooperative Agreement No. 6250-51000-043 and National Institutes of Health grants 5K01DK75489 (XG) and HL51586 (LC). This work is a publication of the USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics,

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    The work was done at the USDA/ARS Children's Nutrition Research Center.

    Conflicts of interest: The authors declare that there are no conflicts of interest associated with this manuscript.

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