You can probably expect to hear a lot about PGC-1-alpha as time goes on because this remarkable substance is turning out to have a lot to do with health and longevity. It appears to be the mediator of the health benefits produced by exercise. This blog post is about PGC-1-alpha, about its relationship to exercise, and about efforts to stimulate it with various substances, in essence seeing if it is possible to provide “exercise in a pill.”
PGC-1-alpha and the PPARG gene
PGC-1-alpha is a gene co-activator, necessary to turn on the PPARG gene and essential in the metabolic process. PGC-1-alpha (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) “is a protein that in humans is encoded by the PPARGC1A gene. The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor PPAR-gamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity(ref).”
The nuclear receptor PPAR-gamma “is a regulator of adipocyte differentiation. — PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. PPAR-gamma agonists have been used in the treatment of dyslipidaemia and hyperglycemia. PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis  (ref).”
Exercise increases PGC-1-alpha expression
In the April 2010 blog entry AMPK and longevity, I touched on the role of AMPK in exercise and quoted the 2009 publication Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle reports “We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle — We conclude that signaling through AMPK and p38 MAPK to PGC-1-alpha may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.”
Production of PGC-1-alpha in cells is stimulated by physical activity and exercise, the presence of cold, glucagon and reactive oxygen species. So, a swim I had last night in the cool waters of Lake Winnipesaukee had a double or triple effect both in making me feel good and rejuvenating my mitochondria with PGC-1-alpha.
PGC-1-alpha in white fat and brown fat
The difference between white fat, based on white adipocytes, and brown fat, based on brown adipocytes, was introduced in the blog entry Getting skinny from brown fat. I said “Brown fat, long known to exist plentifully in babies and rodents, is rich in turned-on mitochondria and blood vessels. Unlike white fat, brown fat burns energy at a ferocious rate. In adults, however, it tends to be scarce and concentrated around the neck and has been traditionally thought to play a relatively minor role in adult human metabolism. The newer research suggests a different picture. Brown fat can be very important for metabolism.” In general, white adipocytes store energy, have few mitochondria, are pro-inflammatory , and manifest in obesity. While brown adipocytes dissipate energy, are dense in mitochondria and function to prevent or reduce obesity. Further, the mitochondria in brown fat contain UCP-1 while those in white fat do not(Note 1). UCP-1 “is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis. Non-shivering thermogenesis is the primary means of heat generation in hibernating mammals and in human infants(ref).”
PGC-1-alpha seems to play important roles in the metabolism of both white and white and brown fat. The 2005 publication PGC-1-alpha, a transcriptional coactivator involved in metabolism states “PPARgamma coactivator-1-alpha (PGC-1-alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1-alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1-alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells.”
PGC-1-alpha turns on the biogenesis of mitochondria primarily in brown fat, working through NRF1, NRF2 and ERRalpha. It promotes fatty acid oxidation working through the PPARs and RXRs, NRF1 and NRF2, combats ROS and promotes glucose utilization, promotes oxidative phosphorylation working via NRF2 and ERRalpha, promotes angiogenesis working through ERRalpha, and contributes to fiber-type switching(Note1).
Effects of elevating the expression of PGC-1-alpha
PGC-1-alpha protects against denervation-induced muscle wasting such as induced by BF-kappaB activation(ref)(note1). Muscle PGC-1alpha blocks age-related obesity and age-related sarcopenia. The 2009 publication Increased muscle PGC-1-alpha expression protects from sarcopenia and metabolic disease during aging highlights the significance of maintaining PGC1-alpha levels for general health and longevity. “Here, we analyzed the effect of mildly increased PGC-1-alpha expression in skeletal muscle during aging. We found that transgenic MCK-PGC-1-alpha animals had preserved mitochondrial function, neuromuscular junctions, and muscle integrity during aging. Increased PGC-1-alpha levels in skeletal muscle prevented muscle wasting by reducing apoptosis, autophagy, and proteasome degradation. The preservation of muscle integrity and function in MCK-PGC-1-alpha animals resulted in significantly improved whole-body health; both the loss of bone mineral density and the increase of systemic chronic inflammation, observed during normal aging, were prevented. Importantly, MCK-PGC-1-alpha animals also showed improved metabolic responses as evident by increased insulin sensitivity and insulin signaling in aged mice. Our results highlight the importance of intact muscle function and metabolism for whole-body homeostasis and indicate that modulation of PGC-1-alpha levels in skeletal muscle presents an avenue for the prevention and treatment of a group of age-related disorders.” Of course, for us non-transgenic humans, the way to maintain the higher PGC1alpha level is exercise.
The 2009 publication PGC-1-alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription relates “Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcriptional coactivator PGC-1-alpha –, which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of transcriptional changes. — Increased expression of PGC-1-alpha also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1-alpha into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1-alpha in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1-alpha during atrophy should enhance the FoxO-dependent loss of muscle mass.”
PGC-1-alpha and muscle fiber type switching
Muscle fibers fall into different type categories which have different properties with respect to mitochondrial content and exercise endurance, and different susceptibilities to obesity and diabetes. Selectively, expression of PGC-1-alpha can influence switching of muscle fibers from one type to another. According to the 2004 publication Regulation of Muscle Fiber Type and Running Endurance by PPARÎ´, “Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor -delta(PPAR-delta) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPAR-delta agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated.”
Further, “Muscle fiber specification appears to be associated with obesity and diabetes. For instance, rodents that gain the most weight on high-fat diets possess fewer type I fibers (Abou et al. 1992). In obese patients, skeletal muscle has been observed to have reduced oxidative capacity, increased glycolytic capacity, and a decreased percentage of type I fibers (Hickey et al. 1995; Tanner et al. 2002). Similar observations have been made in type 2 diabetic patients (Lillioja et al. 1987; Hickey et al. 1995). Recently, it has been shown that increasing oxidative fibers can lead to improved insulin action and reduced adipocyte size (Luquet et al. 2003; Ryder et al. 2003). — Adult skeletal muscle shows plasticity and can undergo conversion between different fiber types in response to exercise training or modulation of motoneuron activity (Booth and Thomason 1991, Jarvis et al. 1996; Pette 1998; Olson and Williams 2000; Hood 2001). This conversion of muscle fiber from type IIb to type IIa and type I is likely to be mediated by a calcium signaling pathway that involves calcineurin, calmodulin-dependent kinase, and the transcriptional cofactor Peroxisome proliferator-activated receptor-gamma coactivator 1Î± (PGC-1Î±) (Naya et al. 2000; Olson and Williams 2000; Lin et al. 2002; Wu et al. 2002)(ref).”
Muscle PGC-1-alpha protects against oxidative damage in aging muscle and PGC-1-alpha prevents age-related loss of endurance running capacity(Note 1).
PGC-1-alpha, insulin resistance and diabetes
Feeding rats a high-fat diet results in the production of more mitochondria, so lack of mitochondria is not responsible for insulin-resistance in this instance. Expression of PGC-1-alpha is responsible for the effect. “It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)delta by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR gamma coactivator 1alpha (PGC-1-alpha) protein expression. Similarly, overexpression of PPARdelta results in a large increase in PGC-1-alpha protein in the absence of any increase in PGC-1-alpha mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARdelta, which mediates a posttranscriptional increase in PGC-1-alpha. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria(ref).”
The discussion in the blog entry Diabetes Part 2: Lifestyle, dietary and supplement interventions relates exercise to the control of diabetes.
Exercise-induced expression of PGC-1-alpha appears to enhance insulin sensitivity, according to the 2010 publication PGC-1-alpharegulation by exercise training and its influences on muscle function and insulin sensitivity. “In contrast, a modest (25%) upregulation of PGC-1, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38MAPK-PGC-1alpharegulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1-alpha, within physiological limits, have revealed its insulin-sensitizing effects.” Thus, it is likely that maintenance of upregulated levels of PGC-1-alpha-is protective against diabetes.
PGC-1-alpha-appears to regulate hundreds of transcription factors. Spiegelman has identified over 120 of them (Note 1).
So, we have a venerable body of conventional wisdom and large population studies supporting the health and longevity effects of regular exercise and now, starting with PGC-1-alpha, an explanation of the molecular and biological mechanisms that produce those health and longevity effects. See the blog entries Exercise, telomerase and telomeres, and On the conventional wisdom of exercise.
(Note 1: a number of the statements in this blog were presented on slides by Bruce L Spiegelman in his presentation last week Control of Aging and Muscle Atrophy by the PGC1 Coactivators at the Ellison Medical Foundation’s Colloquium on the Biology of Aging. Spiegelman has been researching PGC1 coactivators for some time and has contributed to an impressive list of publications related to them. Listening to Spiegelman’s talk inspired me to generate this blog entry.)
Negative effects of PGC-1-beta
I have focused on PGC-1-alpha, but it is worth mentioning that PGC-1-beta is a quite different matter. It appears that consuming saturated fats increases the expression of PGC-1-beta resulting in harmful effects. See for example the 2006 Heartwire item Researchers identify protein that triggers the harmful effects of saturated and trans fatty acids. “Boston, MA – Researchers have identified the molecular mechanism in which the dietary intake of saturated and trans fatty acids results in the elevation of total cholesterol and triglycerides. The target of both saturated and trans fatty acids is PGC-1-beta, a coactivator that alters liver metabolism through a cascade of biochemical signals. — “What we showed was that when you put PGC-1-betainto the liver of an animal, it elevates the secretion of the VLDL particles containing triglycerides and cholesterol,” senior author Dr Bruce Spiegelman (Dana Farber Cancer Institute, Boston, MA) told Heartwire.”
Looking for PGC-1alpha activators
The incredible health-inducing properties of PGC-1-alphahave led to a search for substances that could promote its expression in humans, the idea being to develop a pill that has the positive effects of exercise. Spiegelman reports that his lab at the Dana-Farber Cancer Institute has screened 4,600 bioactive compounds for their ability to induce PGC1alpha in mytotubes. The screen surfaced 36 primary candidates including crinamine, an antibacterial alkaloid present in the crinum asiaticum plant which significantly increased PGc1alpha expression. The candidates screened so far, including crimamine, appeared to be bioactive in other ways and to some extent toxic. Next steps include 1. experiments in aging and mdx mice to see if is possible to activate PGC-1 target genes in-vivo and determine appropriate dosing regimens, 2. screening a larger 54,000 compound library for PGC-1-alpha activators, working with the Broad Institute and 3. collaborating with a large pharmaceutical company to screen additional substances on a very large scale(Note 1).
Meanwhile, my personal response is to continue to exercise, my current target continuing to be a minimum of 47 minutes a day of swimming, treadmilling or hard work like mowing lawns and moving lumber. Having a collection of old buildings on my lake property and a big primary home offers me no end of opportunities for physical work. Viva la PGC-1alpha!