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J Appl Physiol 100: 377-383, 2006. First published October 13, 2005; doi:10.1152/japplphysiol.00781.2005
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Inverse relationship between PGC-1{alpha} protein expression and triacylglycerol accumulation in rodent skeletal muscle

Carley R. Benton,1,3 Xiao-Xia Han,3 Maria Febbraio,2 Terry E. Graham,3 and Arend Bonen3

1Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada; 2Department of Cell Biology, Lerner Research Institute, Cleveland, Ohio; and 3Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

Submitted 1 July 2005 ; accepted in final form 11 October 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
PGC-1{alpha} is a key regulator of tissue metabolism, including skeletal muscle. Because it has been shown that PGC-1{alpha} alters the capacity for lipid metabolism, it is possible that PGC-1{alpha} expression is regulated by the intramuscular lipid milieu. Therefore, we have examined the relationship between PGC-1{alpha} protein expression and the intramuscular fatty acid accumulation in hindlimb muscles of animals in which the capacity for fatty acid accumulation in muscle is increased (Zucker obese rat) or reduced [FAT/CD36 null (KO) mice]. Rates of palmitate incorporation into triacylglycerols were determined in perfused red (RG) and white gastrocnemius (WG) muscles of lean and obese Zucker rats and in perfused RG and WG muscles of FAT/CD36 KO and wild-type (WT) mice. In obese Zucker rats, the rate of palmitate incorporation into triacylglycerol depots in RG and WG muscles were 28 and 24% greater than in lean rats (P < 0.05). In FAT/CD36 KO mice, the rates of palmitate incorporation into triacylglycerol depots were lower in RG (–50%) and WG muscle (–24%) compared with the respective muscles in WT mice (P < 0.05). In the obese animals, PGC-1{alpha} protein content was reduced in both RG (–13%) and WG muscles (–15%) (P < 0.05). In FAT/CD36 KO mice, PGC-1{alpha} protein content was upregulated in both RG (+32%, P < 0.05) and WG muscles (+50%, P < 0.05). In conclusion, from studies in these two animal models, it appears that PGC-1{alpha} protein expression is inversely related to components of intramuscular lipid metabolism, because 1) PGC-1{alpha} protein expression is downregulated when triacylglycerol synthesis rates, an index of intramuscular lipid metabolism, are increased, and 2) PGC-1{alpha} protein expression is upregulated when triacylglycerol synthesis rates are reduced. Therefore, we speculate that the intramuscular lipid sensing may be involved in regulating the protein expression of PGC-1{alpha} in skeletal muscle.

lipid milieu; lipid metabolism

ANTIDIABETIC THIAZOLIDINEDIONES, which activate the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), promote the differentiation of brown adipose cells and their energy expenditure. However, activating PPAR{gamma} by itself failed to activate similar metabolic processes in different cell types (cf. Refs. 3, 49, 53). These observations suggested that in some cells a coactivator was required to realize the full metabolic program that could be achieved by activating PPAR{gamma}. This led directly to the identification of a PPAR{gamma} coactivator (PGC-1{alpha}) (49).

More recently it has been reported that PGC-1{alpha} is expressed in many tissues [liver, heart, kidney, white adipose tissue, and skeletal muscle (3)]. PGC-1{alpha} not only regulates the molecular program that results in adaptive (nonshivering) thermogenesis (49), but it has also been shown to exert profound effects on metabolism, by upregulating mitochondrial biogenesis (35, 65) as well as genes involved with hepatic gluconeogenesis (e.g., PEPCK, G-6-Pase) (29, 50, 67) and muscle glucose transport (42). Genes encoding enzymes involved with mitochondrial fatty acid oxidation (MCAD, M-CPT-1) and oxidative phosphorylation (i.e., citrate synthase, F1–F0 ATP synthase, cytochrome c, cytochrome c oxidase subunits I, II, IV, Va, Vb) appear also to be regulated by PGC-1{alpha} (35, 36, 62, 65). However, more recent studies have shown that the metabolic program in muscle is not always directed solely by PGC-1{alpha} because the expected reductions in the expression of selected genes were not observed in skeletal muscle of PGC-1{alpha} null mice (4), possibly as a result of the unexpected hyperactivity in these animals (39). Nevertheless, in a very short period of time, PGC-1{alpha} has been recognized as a key regulator of tissue metabolism, including skeletal muscle.

In rat skeletal muscle, PGC-1{alpha} expression is greater in oxidative muscles than in glycolytic muscles (33, 38). Under conditions in which mitochondrial biogenesis is induced in skeletal muscle, PGC-1{alpha} expression is also increased, such as during muscle regeneration (16), T3 administration (33), chronic aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside-induced AMPK activation (56, 68), chronic muscle stimulation (33), and exercise training (1, 5, 22, 57). Because it has been shown that PGC-1{alpha} altered the capacity for lipid metabolism (35, 36, 62, 65), it is also possible that the tissue lipid milieu is one of the factors that can influence the expression of PGC-1{alpha}. Several recent studies have provided some indirect evidence for this hypothesis. For example, lipid infusion reduced human skeletal muscle PGC-1{alpha} mRNA by 30% (51), whereas, conversely, reductions in circulating fatty acids increased human muscle PGC-1{alpha} mRNA sixfold (64). However, these very large changes in PGC-1{alpha} mRNA expression were not accompanied by any concurrent changes in PGC-1{alpha} protein expression (64). This may not be surprising, given the complex mechanisms that regulate protein expression, a process that is not only dependent on mRNA abundance (for review, see Refs. 6, 13, 15, 24, 30, 43, 48, 59). In addition, it also seems unlikely that changes in circulating fatty acid concentrations, per se, regulate PGC-1{alpha} expression. Such studies (51, 64) assume that changes in circulating fatty acids result in altered fatty acid metabolism within the muscle, but this has not yet been examined. Thus it is important to determine whether there is a relationship between intramuscular lipid availability and the expression of PGC-1{alpha} at the protein level.

Given that PGC-1{alpha} alters the capacity for lipid metabolism (35, 36, 62, 65) and that muscle cells have fuel-sensing capability (52), we hypothesize that PGC-1{alpha} protein expression is inversely related to the intramuscular lipid milieu. For these purposes, we have examined the relationship between PGC-1{alpha} protein expression and intramuscular fatty acid accumulation in hindlimb muscles of animals in which the capacity for fatty acid accumulation in muscle is either increased [obese Zucker rats (58)] or reduced [FAT/CD36 KO mice (14, 21, 26)]. We observed that PGC-1{alpha} protein expression varies inversely with fatty acid incorporation into intramuscular triacylglycerol depots, an index of intramuscular fatty acid metabolism.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
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 REFERENCES
 
In 8- to 9-wk-old lean (250–281 g) and obese (347–383 g) Zucker male rats (Harlan-Sprague-Dawley, Indianapolis, IN) and in wild-type and FAT/CD36 KO male mice (C57Bl/6, 28–32 g, 4–6 mo of age) (21), we examined in red gastrocnemius (RG) and white gastrocnemius (WG) muscles the protein expression of PGC-1{alpha} and compared it with the abilities of these muscles to accumulate intramuscular triacylglycerol from palmitate. Animals were housed in a controlled environment on a reversed 12:12-h light-dark cycle and fed chow ad libitum (rodent diet 2018, Harlan Teklad, Madison, WI). Animals were anesthetized with an intraperitoneal injection of pentobarbital sodium (6–10 mg/100 g body wt) before any experimental procedures, and they were euthanized with an overdose of pentobarbital sodium. Approval for the studies was obtained from the Animal Ethics Committee at the University of Guelph.

Rates of triacylglycerol accumulation were determined in perfused hindlimb muscles of rats (perfusion flow 17 ml/min) by using established procedures that we have described previously (25, 27, 37, 41). Hindlimb muscles of mice were perfused in an identical manner but at a slower perfusion rate (3 ml/min). Briefly, the hindquarters of rats or mice were preperfused with 0.1% BSA in Krebs-Henseleit buffer (pH 7.4). The medium was gassed continuously with 95% of O2 and 5% of CO2 and maintained at 37°C. Perfusion medium was supplemented with 1-14C-palmitate (0. 5 mM) and glucose (6 mM). After 60 min of perfusion, hindlimb muscles (RG and WG) were removed and frozen in liquid nitrogen and stored at –80°C until analyzed.

Palmitate incorporation into triacylglycerols was determined by thin-layer chromatography, as we have previously described (8, 41). Briefly, frozen muscle (50 mg) was homogenized with a Polytron in 2 ml of 1:1 chloroform-methanol on ice twice, at bursts of 15 s at a speed setting of 8. Solvent solution was recovered by centrifugation at 6,000 g for 10 min at 4°C and transferred to a new tube. The solution was washed with 2 ml of H2O, and the chloroform phase was separated from the aqueous phase with another centrifugation. The chloroform phase containing lipids was stored at –80°C for later analysis. To analyze the intramuscular accumulation of palmitate into the triacylglycerol depots, 500 µl of the chloroform containing lipids was dried under nitrogen and samples were reconstituted with 100 µl of 2:1 chloroform-methanol. A mixture of standard lipids (50 µl) as well as 50 µl of samples were spotted on to 250-mm silica gel plates (Mandel, Guelph, ON, Canada) in separate lanes and resolved in solvent (60:40:3, heptane-isopropylether-acetic acid) for 50 min. Thin-layer chromatography plates were air dried and subsequently sprayed with chlorofluorescein dye (0.02% wt/vol in ethanol). Triacylglycerol bands were visualized under long-wave UV light against standards and marked precisely. The silica gel powder of the individual band was carefully scraped off and transferred into scintillation cocktail for counting the 14C-palmitate incorporation into muscle triacylglycerols.

By using procedures previously described in our laboratory (9, 12, 40), proteins were separated by SDS-PAGE and PGC-1{alpha} was detected with Western blotting procedures.

From separate groups of anesthetized rats and mice, we obtained tail vein blood samples, as well as RG and WG muscle samples. Serum samples were analyzed for glucose by a spectrophotometric method (Sigma, St. Louis, MO). Fatty acid concentrations were determined by a spectrophotometric procedure (Wako Chemicals, Richmond, VA). PGC-1{alpha} protein was determined by standard Western blotting procedures as performed in our previous work (7, 9–11). Briefly, membranes were blocked for 1 h at 4°C in 10% nonfat milk in 1x Tris-buffered saline Tween (TBS-T), before being incubated with PGC-1{alpha} (Calbiochem, San Diego, CA; 1:1,000 10% nonfat milk in TBS-T), for 1 h at 4°C. After washes with 1x TBS-T, the secondary antibody (1:1,000 donkey anti-rabbit HRP-IgG; GE Healthcare, Baie d’Urfe, Quebec, Canada) was applied for 1 h at 4°C. Signals obtained by Western blotting using enhanced chemiluminescence (Perkin-Elmer, Woodbridge, ON, Canada) were quantified by densitometry as per the manufacturer’s instructions (SynGene, ChemiGenius2, Perkin-Elmer).

The data were analyzed with analyses of variance and Fisher’s least squares difference post hoc test, using a commercially available statistical package (Statview). All data are reported as means ± SD.


   RESULTS
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In the rats, nonfasting glucose concentrations were similar in lean and obese animals, whereas fatty acid concentrations were 3.2-fold greater in the obese rats than in the lean animals (Table 1). This corresponds to a previous report from our laboratory (40).


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  		Table 1. Glucose and fatty acid concentrations in anesthetized, nonfasted lean and obese Zucker rats and in nonfasted WT and KO mice

 
In the mice, nonfasting glucose concentrations were also similar in WT and FAT/CD36 KO mice, but fatty acid concentrations were 30% higher in the KO mice than in WT mice (Table 1). In other studies in fed mice, fatty acid concentrations did not differ between WT and FAT/CD36 KO mice (14), whereas in fasted mice fatty acid concentrations were markedly increased (+90%) in FAT/CD36 KO mice but glucose concentrations (–42%) were reduced compared with WT mice (14, 23).

Lean and obese Zucker rats.   In both lean and obese Zucker rats, there were marked differences in the rates of palmitate incorporation into RG and WG triacylglycerol depots. In the lean animals, the rates were 5.6-fold greater in RG compared with WG (P < 0.05, Fig. 1). A similar difference (5.7-fold) was observed between RG and WG muscle (P < 0.05, Fig. 1) in the obese animals. The rate of palmitate incorporation into triacylglycerol depots in obese rats was greater in RG (28%) and WG muscles (24%) compared with the respective muscles in lean rats (P < 0.05, Fig. 1).


Figure 1
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  		Fig. 1. Rate of palmitate incorporation into triacylglycerol depots in red (A) and white gastrocnemius muscles (B) of lean and obese Zucker rats and wild-type (WT) and FAT/CD36 null (KO) mice. Data are means ± SD. N = 5 lean and N = 5 obese rats; N = 5 WT and N = 5 KO mice. Statistical analyses were performed within each group (i.e., lean vs. obese rats; WT vs. KO mice), not between groups. *P < 0.05, white vs. red gastrocnemius muscle within each group; **P < 0.05 obese vs. lean, or WT vs. KO.

 
PGC-1{alpha} protein concentrations were greater in RG than in WG, in both lean (+57%, P < 0.05, Fig. 2) and obese animals (+61%, P < 0.05, Fig. 2). In the obese animals, PGC-1{alpha} protein content was lower in both RG (–13%) and WG muscles (–15%) (P < 0.05, Fig. 2).


Figure 2
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  		Fig. 2. PGC-1{alpha} protein content in red (A) and white gastrocnemius muscles (B) of lean and obese Zucker rats and WT and KO mice. Data are means ± SD. N = 5 lean and N = 5 obese rats; N = 5 WT and N = 5 KO mice. Statistical analyses were performed within each group using ANOVA (i.e., lean vs. obese rats; WT vs. KO mice), not between groups. *P < 0.05, white vs. red gastrocnemius muscle within each group; **P < 0.05, ANOVA: obese (red and white muscles) vs. lean (red and white muscles), or WT (red and white muscles) vs. KO (red and white muscles).

 
FAT/CD36 wild-type and KO mice.   The rates of palmitate incorporation into triacylglycerol depots in RG were greater than in WG muscle of the wild-type mice (P < 0.05, Fig. 1). Similarly, in the KO mice, these rates were also greater in RG compared with WG muscles (P < 0.05, Fig. 1). However, in KO mice compared with WT mice, the rates of palmitate incorporation into triacylglycerol depots in both RG (–50%) and WG (–25%) were reduced (P < 0.05, Fig. 3B).


Figure 3
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  		Fig. 3. Net mean differences (%) in triacylglycerol (TAG) formation from palmitate and PGC-1{alpha} protein in red (A) and white gastrocnemius muscles (B) of lean and obese Zucker rats and WT and KO mice. Data are calculated from the means of the data in Figs. 1 and 2.

 
PGC-1{alpha} protein content was greater in RG compared with WG in both wild-type mice and FAT/CD36 KO mice (P < 0.05, Fig. 2). However, in FAT/CD36 KO mice, PGC-1{alpha} protein content was upregulated in both RG (+32%, P < 0.05, Fig. 2A) and WG (+50%, P < 0.05, Fig. 2B).

Changes in intramuscular triacylglycerol accumulation and PGC-1{alpha} protein.   Because there were differences in the rates of palmitate incorporation into triacylglycerol depots and PGC-1{alpha} content in muscle of Zucker obese rats and FAT/CD36 KO mice, we compared the relative changes (%) in these parameters in the RG and WG muscles of these two groups of animals. It is evident that in Zucker obese rat muscles the greater rates of palmitate incorporation into triacylglycerol depots were associated with concurrent reductions in PGC-1{alpha} (Fig. 3). Conversely, in the FAT/CD36 KO mice, the lower rates of palmitate incorporation into triacylglycerol depots were associated with concurrent increases in PGC-1{alpha} in RG and WG muscles (Fig. 3).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Because PGC-1{alpha} is known to alter the capacity for lipid metabolism (35, 36, 62, 65), we hypothesized that PGC-1{alpha} protein expression is inversely related to the intramuscular lipid milieu. To examine this possibility, we compared the rates of PGC-1{alpha} protein expression in animal models that were known to have different capacities for intramuscular accumulation of fatty acids, namely 1) the obese Zucker rat, in which fatty acid uptake and accumulation are markedly upregulated compared with lean Zucker rats (58), and 2) FAT/CD36 KO mice, in which fatty acid uptake and metabolism are reduced compared with wild-type mice (14, 21, 26). We observed that 1) when rates of fatty acid accumulation in triacylglycerol depots are increased, PGC-1{alpha} protein content in muscle is reduced (obese Zucker rats) and 2) conversely, when fatty acid accumulation in triacylglycerol depots is reduced, PGC-1{alpha} protein content in muscle is increased (FAT/CD36 KO mice). These opposite changes in PGC-1{alpha} protein content in muscles of obese Zucker rats and FAT/CD36 null mice are unrelated to the circulating fatty acids, because these were increased in both the obese Zucker rats and in the FAT/CD36 null mice. Taken altogether, these data appear to suggest that "lipid sensing" within muscle may provide signals that contribute to the regulation of PGC-1{alpha} protein expression.

We have shown previously in obese Zucker rats that the increased sarcolemmal content of FAT/CD36 increases the rate of palmitate transport into muscle (40), and this augmented influx would seem to contribute to the accretion of triacylglycerols in this model, as fatty acid oxidation is not altered (58). Conversely, FAT/CD36 KO mice have a lower rate of skeletal muscle fatty acid uptake (14), and this contributes to a reduced ability to synthesize triacylglycerol from palmitate within the muscle (26). In the present studies, we have confirmed that the rates of triacylglycerol synthesis are increased in obese Zucker rat muscle (58) and reduced in the muscles of FAT/CD36 KO muscle (26). In addition, we also confirmed the well-known differences in the rates of triacylglycerol synthesis between red and white muscles (17) in lean and obese rats (58) and in wild-type and FAT/CD36 KO mice (26).

The inverse relationship between the intramuscular lipid milieu and PGC-1{alpha} protein expression observed in the present study parallels recent linkages observed in humans and animals between the muscles’ lipid milieu and PGC-1{alpha} expression. In humans, increasing circulating fatty acid concentrations (48 h) repressed PGC-1{alpha} mRNA by 30% (51), whereas, in contrast, PGC-1{alpha} mRNA was increased sixfold when circulating fatty acids were reduced (64). In an animal model in which circulating fatty acids are increased (Zucker diabetic fatty rats), skeletal muscle PGC-1{alpha} mRNA was reduced by 41% (34). Finally, in a model in which intramuscular triacylglycerol depots are increased (high-fat feeding) skeletal muscle PGC-1{alpha} mRNA expression was reduced in both men (–20% in 3 days) and in mice (–90% in 3 wk) (55). Thus it appears that PGC-1{alpha} expression in skeletal muscle is inversely related to the lipid milieu in this tissue. Importantly, the specific mechanisms by which fatty acids regulate PGC-1{alpha} mRNA expression have not yet been identified in any of these studies (34, 51, 55, 64). In addition, it has been assumed that altering the circulating concentration of fatty acids (34, 51, 64) or high-fat feeding (55) somehow alters intramuscular fatty acid metabolism and that this influences the regulation of PGC-1{alpha} expression. However, no previous study has yet examined a linkage between altered intramuscular fatty acid metabolism and PGC-1{alpha} expression.

The present study is the first to examine the different capacities for triacylglycerol accumulation (an index of intramuscular fatty acid metabolism) with changes in PGC-1{alpha} protein expression. As a first step, we compared this relationship in animal models with different capacities for fatty acid metabolism. It is recognized that other factors may possibly have contributed to the different levels of PGC-1{alpha} observed in these animal models. However, this same limitation applies to all other published studies in which the muscles’ lipid milieu has been altered (34, 51, 55, 64), as altering the circulating concentrations of fatty acids or high-fat feeding may also alter the concentrations of insulin, epinephrine, and glucose. Thus it needs to be recognized that in these types of experiments one or more of these factors [e.g., epinephrine (64)], as well as the altered lipid milieu, may also contribute to regulating the expression of PGC-1{alpha} mRNA.

Another important aspect of the present study is that we examined the PGC-1{alpha} protein rather than PGC-1{alpha} mRNA. Changes in PGC-1{alpha} mRNA and PGC-1{alpha} protein do not necessarily correlate. Some have shown that a sixfold increase in PGC-1{alpha} mRNA was not accompanied by any changes in PGC-1{alpha} protein (64), whereas others have shown a qualitative relationship between changes in PGC-1{alpha} protein (–40%) and PGC-1{alpha} mRNA (–90%) in high-fat-fed mice (55). These studies indicates that changes in PGC-1{alpha} mRNA cannot always be used reliably as an indicator of changes in PGC-1{alpha} protein. This may not be surprising given the complex mechanisms that regulate protein expression, a process that is not dependent on mRNA abundance only (for review, see Refs. 6, 13, 15, 24, 30, 43, 48, 59). From a physiological perspective, it is necessary to ascertain changes at the level of protein expression, because it is the PGC-1{alpha} protein, not the PGC-1{alpha} transcripts, that activate PPAR{gamma}. The present study and the recent study by Sparks et al. (55) are the first to observe that PGC-1{alpha} protein expression is downregulated when the intramuscular lipid accretion is upregulated.

The present study is also the first to observe the converse, namely that PGC-1{alpha} protein expression is increased when skeletal muscle triacylglycerol synthesis is reduced. This impaired skeletal muscle triacylglycerol synthesis in FAT/CD36 KO mice has been linked to a reduced capacity for fatty acid uptake into the muscle of these mice (26). The increased content of PGC-1{alpha} protein in the face of a reduced triacylglycerol accumulation supports our hypothesis that PGC-1{alpha} expression is linked with the lipid milieu within the muscle. Thus we speculate that muscle appears to be sensing its lipid milieu and in this manner may be regulating PGC-1{alpha} expression inversely with lipid availability.

It is important to note that we do not assume that intramuscular triacylglycerol depots "cause" alterations in PGC-1{alpha} protein expression. Instead, we have used the rate of palmitate incorporation into triacylglycerol depots as an index of the lipid milieu within the muscle. Triacylglycerol depots in muscle are quantitatively a major destination for fatty acids (17–19), and we have shown that the rate of palmitate incorporation into triacylglycerols correlates well with both fatty acid entry and triacylglycerol concentrations in muscle (11). The rate of radiolabeled palmitate incorporation into triacylglycerol depots provides a more sensitive measure of the muscle’s ability to accumulate lipids (17–19) than the highly variable, enzymatic determination of triacylglycerol concentrations (cf. Ref. 63). We believe that the accretion of triacylglycerols serves as a surrogate measure of the lipid products within mammalian muscle. These products may include ceramides or diacylglycerols or long-chain fatty acyl CoAs. Indeed, recent work in our laboratory has shown a good relationship between triacylglycerol, diacylglycerol, and ceramide concentrations in muscle (2). In contrast to intramuscular triacylglycerols, fatty acid oxidation is not a particularly good surrogate measure of altered lipid intermediates in muscle cells, because rates of altered fatty acid oxidation appear to depend on the degree of obesity (11, 31), nor is there a good correlation between skeletal muscle fatty acid oxidation and intramuscular concentrations of lipid intermediates such as diacylglycerols or ceramides (2). The use of intramuscular triacylglycerol as a surrogate measure of intramuscular lipid metabolism in the present study parallels very closely the approach that has been used by a great many groups in recent years to link alterations in insulin sensitivity to changes in intramuscular triacylglycerol concentration, with the realization that this measure likely serves as a surrogate for other lipid products that interfere with insulin signaling (cf. Ref. 54).

The mechanism(s) accounting for the lipid-mediated changes in PGC-1{alpha} remains unknown, but given the present results it is possible to speculate about these. It is well known that fatty acids can alter gene expression (32, 60). However, it is likely that the fatty acid derivatives such as diacylglycerols and ceramides are key, as intramuscular fatty acids are very rapidly metabolized and thus intramuscular fatty acid concentrations are extremely low (61). We assume that their concentrations were increased in obese Zucker rat muscle and reduced in muscles of FAT/CD36 KO mice, as would seem to be suggested by the changes in fatty acid incorporation into triacylglycerols, the surrogate measure of intramuscular lipid metabolites in this and other studies (e.g., Refs. 20, 28, 44–47, 66). On the basis of these arguments, we speculate that the increase in intramuscular lipid metabolites represses PGC-1{alpha} protein expression, whereas a reduction in intramuscular lipid metabolites stimulates PGC-1{alpha} protein expression. We further suspect that lipid metabolites act at the transcriptional level (32), given the profound effects of altered concentrations of circulating fatty acids on PGC-1{alpha} mRNA expression (51, 64).

In summary, we have shown in skeletal muscle that 1) PGC-1{alpha} protein expression is downregulated when triacylglycerol synthesis rates, an index of intramuscular lipid accumulation, are increased and 2) PGC-1{alpha} protein expression is upregulated when triacylglycerol synthesis rates are reduced. Therefore, we propose that intramuscular lipid sensing is involved in regulating the protein expression of PGC-1{alpha}.


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These studies were supported the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

A. Bonen is Canada Research Chair in Metabolism and Health.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Bonen, Dept. of Human Health and Nutritional Sciences, Univ. of Guelph, Guelph, Ontario, Canada N1G 2W1 (e-mail: abonen{at}uoguelph.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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