Skeletal muscle heterogeneity in fasting-induced upregulation of genes encoding UCP2, UCP3, PPARγ and key enzymes of lipid oxidation

Abstract

The uncoupling protein homologs UCP2 and UCP3 have been proposed as candidate genes for the regulation of lipid metabolism. Within the context of this hypothesis, we have compared, from fed and fasted rats, changes in gene expression of skeletal muscle UCP2 and UCP3 with those of carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase, two key enzymes regulating lipid flux across the mitochondrial beta-oxidation pathway. In addition, changes in gene expression of peroxisome proliferator-activated receptor gamma, a nuclear transcription factor implicated in lipid metabolism, were also investigated. The results indicate that in response to fasting, the mRNA levels of UCP2, UCP3, carnitine palmitoyltransferase I and medium-chain acyl-CoA dehydrogenase are markedly increased, by three- to sevenfold, in the gastrocnemius and tibialis anterior (fast-twitch muscles, predominantly glycolytic or oxidative-glycolytic), but only mildly increased, by less than twofold, in the soleus (slow-twitch muscle, predominantly oxidative). Furthermore, such muscle-type dependency in fasting-induced transcriptional changes in UCP2, UCP3, carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase persists when the increase in circulating levels of free fatty acids during fasting is abolished by the anti-lipolytic agent nicotinic acid - with blunted responses only in the slow-twitch muscle contrasting with unabated increases in fast-twitch muscles. Independently of muscle type, however, the mRNA levels of peroxisome proliferator-activated receptor gamma are not altered during fasting. Taken together, these studies indicate a close association between fasting-induced changes in UCP2 and UCP3 gene expression with those of key regulators of lipid oxidation, and are hence consistent with the hypothesis that these UCP homologs may be involved in the regulation of lipid metabolism. Furthermore, they suggest that in response to fasting, neither the surge of free fatty acids in the circulation nor induction of the peroxisome proliferator-activated receptor gamma gene may be required for the marked upregulation of genes encoding the UCP homologs and key enzymes regulating lipid oxidation in fast-twitch muscles.

Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

“…These effects are especially observed in the gastrocnemius muscle, a fast-twitch muscle that is predominantly glycolytic. Similar variations are observed in the food-restricted condition (Samec et al, 2002). Finally, Pardo et al (2010) describe, in the ABA model, a tissue-specific expression pattern of GHS-R1a receptors in visceral and subcutaneous fat and within the muscle.…”

Dietary Enrichment with Fish Oil Prevents High Fat-Induced Metabolic Dysfunction in Skeletal Muscle in Mice

“…Whether n-3 PUFAs from natural fish oil abrogate intramyocellular lipid accumulation in a HF-S setting is unclear and the pathways involved require clarification. Additionally, the vast majority of past studies have examined only the effect of dietary n-3 PUFA supplementation in either white glycolytic skeletal muscles [ 24 ] or muscles of mixed fiber type [ 25 – 30 ] that are reliant on glucose or a fuel mixture as their main substrate [ 31 ]. Red fibers are oxidative and rely heavily on lipids as fuel [ 31 – 33 ].…”

“…Additionally, the vast majority of past studies have examined only the effect of dietary n-3 PUFA supplementation in either white glycolytic skeletal muscles [ 24 ] or muscles of mixed fiber type [ 25 – 30 ] that are reliant on glucose or a fuel mixture as their main substrate [ 31 ]. Red fibers are oxidative and rely heavily on lipids as fuel [ 31 – 33 ]. The extent to which the addition of n-3 PUFAs to a HF-S diet modifies lipid metabolism in these red fibers remains to be determined, although increased Cpt1b and Ucp3 mRNA have been reported in the mouse soleus in response to EPA ethyl ester enrichment of a high fat diet [ 34 ].…”

Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner

“…Glycolytic muscles are mainly composed of fast twitch or fast glycolytic fibres and generate energy by means of anaerobic metabolic processes, whereas oxidative muscles have a high proportion of slow twitch or slow oxidative fibres, are very resistant to fatigue and obtain energy through oxidative metabolic processes [5,6]. Under normal feeding conditions, glycolytic muscles use mainly glucose metabolism, whereas oxidative muscles are highly dependent upon lipids [7]. Because of the differences between muscle types in energy demand and reliance on mitochondrial oxidative activity, differences in mitochondrial function can not be ruled out.…”