Peroxisome Proliferator-activated Receptor-γ Co-activator 1α-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency

Abstract

Peroxisome proliferator-activated receptor-␥ co-activator 1␣ (PGC1␣) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1␣ activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of ␤-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1␣. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1␣ expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1␣, provokes a disconnect between mitochondrial ␤-oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1␣ overexpression favored a shift from incomplete to complete ␤-oxidation. We proposed that PGC1␣ enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.Obesity and type 2 diabetes are two closely associated diseases that continue to affect Westernized societies at epidemic rates (1). Results from both epidemiological and animal studies suggest that the risk of developing these diseases is increased by consumption of a high fat diet (2), which has been attributed in part to increased intramuscular triacylglycerol storage and adverse changes in skeletal muscle energy metabolism (3). Moreover, mounting evidence from animal and cellbased models indicates that lipid oversupply to skeletal muscle results in functional perturbations that eventually manifest as impaired insulin action (2, 4, 5). Together, these and other reports have established a compelling connection between muscle lipid dysregulation and impaired metabolic control at both the cellular and systemic levels. Despite intense investigation, a clear understanding of the biochemical and molecular mechanisms that mediate lipid-induced muscle dysfunction has remained elusive.Similar to high fat feeding, exercise training increases skeletal muscle supply and storage of lipid substrates (6). However, in contrast to the adverse events provoked by a high fat diet, exercise is known to promote muscle as well as whole body metabolic fitness (7). These observations suggest that physical activity somehow enhances the capacity of the muscle to tolerate and/or adapt to a high lipid load. Indeed, contractile activity leads to dramatic adjustments in oxidative fuel metabolism that are largely mediated by an increase in muscle mitochondria...

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control

“…Still unclear is whether poor mitochondrial performance is a predisposing factor or a consequence of the disease process. The latter view is supported by recent animal studies linking diet-induced insulin resistance to a dysregulated mitochondrial phenotype in skeletal muscle, marked by excessive ␤-oxidation, impaired substrate switching during the fasted to fed transition, and coincident reduction of organic acid intermediates of the tricarboxylic acid cycle (4,5). In these studies, both diet-induced and genetic forms of insulin resistance were specifically linked to high rates of incomplete fat oxidation and intramuscular accumulation of fatty acylcarnitines, byproducts of lipid catabolism that are produced under conditions of metabolic stress (5,6).…”

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…The correlations between PGC-1α and rodent muscle oxidative capacity, and between PGC-1α and both GLUT4 and FAT support the idea that in lean and obese muscles PGC-1α is central to a coordinated metabolic programme that upregulates a number of genes simultaneously to produce an oxidative muscle phenotype that relies extensively on blood-borne substrates for energy provision [3,5,31]. The small range of PGC-1α protein abundance across a range of heterogeneous muscles implies that small, physiologically induced changes in PGC-1α protein [6,30,32,33] can have pronounced effects on muscle metabolism, as shown by the present study and others [3,16].…”

“…In muscle cell lines, increased levels of PGC-1α induced insulin-sensitising effects via the upregulation of selected genes involved in fatty acid β-oxidation, glucose transport and oxidative phosphorylation [6,7], while in type 2 diabetes, muscle PGC-1α expression was reduced [8,9]. Collectively, these studies suggest that PGC-1α may be a key factor regulating insulin sensitivity in mammalian muscle [5][6][7][8][9]. However, experimental studies in vivo have been disappointing.…”

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

“…However, although much is known about the physiological stimuli that increase PGC-1α content in muscle, the in vivo regulation of PGC-1β is less well understood. Indeed, there is substantial disparity in the literature in this regard, with some studies reporting no alterations in PGC-1β levels with denervation, exercise or obesity [40,41], whereas others have shown two-to threefold increases in PGC-1β expression in muscle with diverse stimuli, including insulin stimulation [21], exercise [42], bariatric surgery [43], dietary restriction [44] and treatment with the adipokine apelin [45]. In the present study we also observed a twofold increase in Pgc-1β in rat TC muscle following 4 weeks of an HFD.…”