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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 2, 2003 as doi:10.1096/fj.03-0269fje. |
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controls muscle development and oxidative capability1
* Inserm U470, Centre de Biochimie, Parc Valrose, Université de Nice-Sophia Antipolis, 06108 Nice cedex 2, France;
# Service de Diabétologie-Endocrinologie, Hôpital Pasteur, 06002 Nice, France; and
Inserm EMI-9913, Genopole, 91057 Evry, France
2Correspondence: E-mail: grimaldi{at}unice.fr
SPECIFIC AIMS
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for lipid molecules that exert regulatory functions in development and metabolism. To investigate the specific functions of PPAR
in skeletal muscle development and lipid metabolism, we used a CRE-Lox recombination approach to generate an animal model for specific overexpression of the nuclear receptor in this tissue.
PRINCIPAL FINDINGS
1. Establishment of an animal model for muscle-specific overexpression of PPAR
We generated mouse lines harboring a transgene consisting of the mouse PPAR coding sequence under the control of the ubiquitously expressed CAG promoter. A transcriptional Stop cassette flanked by two LoxP sites was inserted between the promoter and the PPAR sequence to block transcription. To promote excision of the Stop cassette specifically in muscle, these transgenic mice were crossed with human skeletal actin-Cre (HSA-Cre) mice exhibiting muscle-restricted expression of Cre in adult animals. Analysis of tissue distribution of transgenic PPAR mRNA revealed that double-transgenic animals (i.e., harboring both Cre and PPAR transgenes) display strong PPAR mRNA signals in different muscles, whereas no signal was detected in other tissues. As expected, control animals (nontransgenic or harboring only one of the transgenes) did not express the transgenic RNA whatever tissue was examined. Western blot analysis showed that in various muscles, such as soleus, tibialis anterior, and plantaris, the content of PPAR protein was increased by up to sixfold and that this increase was similar in the other muscles studied.
2. Muscle-specific overexpression induces a shift toward more oxidative fibers
No significant effects of PPAR overexpression on weight or cross section area of different muscles were observed whatever the age of the animals. However, histological analysis showed that the number of succinate dehydrogenase (SDH)-positive fibers was considerably increased in muscles from double-transgenic mice compared with their control littermates. This remodeling is due to hyperplasia and/or shift of SDH-negative to SDH-positive fibers. Muscle remodeling was especially impressive in tibialis anterior, with an increase of 2.7-fold in SDH-positive fibers (Fig. 1
). These histological observations were confirmed by the finding that muscle-specific PPAR overexpression led to a 1.5-fold increase in tibialis anterior muscle of other oxidative enzymatic activities such as citrate synthase (CS) and ß-hydroxyacyl-CoA dehydrogenase (BOAC). Conversely, activities of glycolytic enzymes such as glycerophosphate dehydrogenase and lactate dehydrogenase remained unchanged. Northern blot analysis revealed that uncoupling protein 2 mRNA (UCP-2) and heart fatty acid binding protein (H-FABP) mRNA, both encoding proteins involved in fatty acid catabolism, were up-regulated by 1.9-fold and 2.1-fold, respectively, in muscle from double-transgenic mice vs. control littermates. Collectively, these data demonstrated that muscle-specific PPAR overexpression increases muscle oxidative capability.
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3. Muscle-specific PPAR overexpression promotes a decrease of body fat content
Analysis of individual fat pad weights revealed a 3- and 2.6-fold reduction of periovarian and dorsal pad weights, respectively, in adult double-transgenic animals compared with control littermates. A more detailed analysis was carried out to characterize the effects of muscle-specific PPAR overexpression on cell size distribution of adipocytes from the periovarian pads of 2-month-old mice. As shown in Fig. 2
, muscle-specific PPAR overexpression promoted a shift toward smaller adipocyte size. Mean adipose cell diameter is 54.4 µm in double-transgenic animals vs. 72.2 µm in control littermates. Such a difference in cell size could account for the reduction in adipose pad weights, suggesting that total cell number was unchanged in PPAR overexpressing animals.
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4. Exercise up-regulates muscle PPAR protein amount in wild-type mice
Muscle remodeling promoted by muscle-specific PPAR overexpression is in some ways reminiscent of that provoked by endurance training. It is tempting to speculate that PPAR could be involved in exercise-promoted muscle remodeling. To explore this hypothesis, we quantified the PPAR protein content in muscles from wild-type mice trained or not. Our data showed that 3 wk of moderate exercise (a 45 min swim per day, 5 days/wk) increased the amount of PPAR protein in the plantaris muscle by 1.26 ± 0.06-fold (P<0.001, n=4) compared with untrained animals. This increase in PPAR protein muscle content was more impressive after 6 wk of training, reaching 2.686 ± 0.338-fold (P<0.015, n=4). These observations argue in favor of a role of PPAR as a mediator of adaptive response of muscle to exercise.
CONCLUSIONS
PPAR is expressed in a variety of tissues and is activated by long chain fatty acids, prostacyclin, and newly described synthetic molecules that normalize both hypertriglyceridemia and hyperinsulinemia in obese animals. To investigate the role of PPAR in skeletal muscle, a major organ for lipid metabolism, we generated a murine model for a muscle-specific overexpression of the nuclear receptor using a Cre-Lox approach. We demonstrate that overexpression of PPAR in skeletal muscle greatly influenced both development and metabolism capability of mouse muscles by promoting a net increase of fibers with oxidative metabolic capabilities. This increase is related to both hyperplasia and shift from glycolytic to oxidative fibers. The consequence of this muscle remodeling is an increase of oxidative enzymatic activities, such as CS and BOAC, and up-regulation of genes such as UCP-2 and H-FABP. Conversion of glycolytic fibers to oxidative fibers has already been reported in animals overexpressing PPAR
coactivator-1 (PGC-1), a master regulator of mitochondrial biogenesis. However, overexpression of PGC-1 leads to a complete conversion of fast-twitch to slow-twitch fibers, while overexpression of PPAR does not promote appearance of actual type I fibers in tibialis anterior or plantaris muscle. Muscle remodeling induced by PPAR overexpression is reminiscent of that promoted by endurance training, which is also characterized by hyperplasia, with increment of oxidative fiber number leading to an up-regulation of oxidative capabilities. The finding that exercise up-regulates PPAR content in muscle favors a model in which the nuclear receptor plays a causal role in the increase of oxidative fiber number. Another common mark of exercise and muscle PPAR overexpression is the reduction of body fat content by a decrease in adipocyte size. This process could be due to an increase of the metabolic flux toward muscle limiting fatty acid supply for triacylglycerol synthesis in adipose tissue, or to an increment of production by skeletal muscle of signaling factors affecting adipose lipid accumulation (Fig. 3
). Whatever the mechanisms underlying this reduction of fat stores, it can be predicted that muscle PPAR overexpressing animals will be protected against devel-opment of insulin resistance, as it is now known that small adipocytes increase insulin sensitivity, probably by secreting more adipocytokines such as adiponectin.
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In conclusion, our data strongly suggest a role for PPAR in muscle development and adaptive response of muscle to environmental changes. These data also raised the possibility that as a receptor, PPAR could be targeted by a specific agonist in skeletal muscle in order to prevent metabolic disorders, such as insulin resistance and obesity, by increasing catabolism of lipid in muscle and decreasing lipid accumulation in adipose tissue.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0269fje; 
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