Imagine a muscular switch that can convert easily fatigued "fast-twitch" muscle fibers into the lean, oxygen-fueled fibers that enable joggers to run for hours.
This long-sought switch is a protein called PGC-1-alpha, discovered in the late 1990s by cell biologist Bruce Spiegelman at the Harvard-affiliated Dana-Farber Cancer Institute in Boston. "PGC-1," he foresees, "might some day enable physicians to give patients weakened by disease a drug to build up muscular endurance without exercise. Normally," he pointed out, "the only way to achieve this muscular reprogramming is through lengthy, demanding training regimens."
Spiegelman is senior author of a paper in the current issue of Nature, dated Aug. 15, 2002. Its title: "Transcriptional co-activator PGC-1a drives the formation of slow-twitch muscle fibers."
"Our findings," he stated, "describe the pivotal role of PGC-1 in transforming fast-twitch fibers to slow-twitch fibers. Fast-twitch fibers," he added, "create the bulkier, strong but quickly fatigued muscles of weightlifters or sprinters. Most muscles contain a combination of the two fibers, Types I and II. PGC-1," Spiegelman continued, "appears to be the switch, or a major component of it, that enables your body's muscles to adjust to the demands being put on them. Understanding how this system works could make it possible to develop a drug to manipulate this system."
Endocrinologist Bradford Lowell is a co-author of the Nature paper. He was responsible for creating the line of transgenic mice used in the project. "Basically," he told BioWorld Today, "a DNA construct was prepared, using a gene muscle promoter to drive overexpression of PGC-1-alpha in muscle. We used this construct to generate lines of transgenic mice. In these mice, PGC-1 expressed at a higher amount than is typical, and the end result was that this converted the muscle fibers from what's called white' to red,' or red fiber type.' These are the fiber types that tend to be more abundant in long-distance runners, as opposed to sprinters, who have more white fiber type.'"
PGC Protein Conducts Muscular Orchestra
"The acronym for PGC," Lowell explained, "is an acronym upon acronym. The p' stands for PPAR, the g' for gamma, and the c' is the co-activator. The team had previously identified a transcriptional co-activator, which is expressed in several tissues, including brown fat and skeletal muscle. It activates mitochondrial biogenesis and oxidative metabolism. Their data indicate that PGC-1-alpha is a principal factor regulating muscle fiber type determination."
Spiegelman and his co-authors had previously shown that PGC-1 acts as a switch in the liver to regulate the manufacture of glucose, which fuels the body's cells. In their present skeletal-muscle research, they found PGC-1 to have a somewhat similar function: It triggers the development of mitochondria - the cells' power-plant organelles - that give slow-twitch fibers their extraordinary endurance. At the same time, the process turned on by PGC-1 produces proteins such as myoglobin that slow-twitch muscles require. Myoglobin is the oxygen-carrying and storage protein of muscle, which in function resembles blood hemoglobin.
PGC-1 is naturally expressed - or active - in skeletal and heart muscle. Spiegelman's team found that it is expressed at higher levels in muscles containing a lot of Type I fibers. Fibers exposed to PGC-1 had more mitochondria, normally in Type I fibers. Those fibers use the mitochondria and oxygen as a source of energy - as in aerobic exercise. In contrast, Type II, fast-twitch fibers get their energy mainly from the breakdown of glucose - that is, sugar.
To assess the role for PGC-1-alpha in myofiber specification, Lowell and his co-authors created transgenic mice that expressed the PGC-1 gene in all their skeletal muscles. The DNA promoter MCK (muscle creatine kinase) that they added activated the gene in Type II muscle fibers as well as Type I. The transgenic mice produced the slow-twitch PGC-1 protein, which switches on mitochondrial proliferation and metabolism in muscle cells that are normally fast-twitch. The animals' muscle fibers converted to slow-twitch, so were more resistant to fatigue.
For gene expression analysis, muscles were dissected from 3-month-old wild-type or transgenic mice. Molecular biologist Eric Olson, at the University of Texas Southwestern in Dallas, is a co-author of the paper. "When we studied the bioengineered rodents, we found that the muscles normally rich in Type II fibers now had a characteristically reddish color, characteristic of oxidative muscle - recalling iron rust - caused by the conversion of the Type II fibers to oxygen-fueled Type I. The muscles of non-transgenic littermates were paler in appearance - like the white meat of a chicken. Moreover, an in vitro endurance test showed that the muscles treated with PGC-1 genes contracted efficiently for seven minutes, while muscles from untreated mice performed well for only about two minutes."
The Nature paper makes the point, "There had not been described to date a transcriptional component that could potentially integrate calcium signaling [by calcineurin], mitochondrial biogenesis and these myofibrillar protein regulators."
No Muscle-Boosting Drug In View - Yet
Adult skeletal muscle allows conversion of different fiber types in response to chronic change in contractile demand. For example, repeated mechanical overload and endurance training increased the percentage of Type I fibers.
While the researchers caution that they are not promising a new athletic stamina-enhancing drug, they say, "It's certainly possible that these findings might benefit people who are deficient in Type I muscle fibers because of medical conditions." Molecular biologist Rhonda Bassel-Duby, at the University of Texas Southwestern at Dallas, a co-author, observed: "Down the road, one would like to be able to incorporate it into some therapy where one had diseased muscles. One possibility," she suggested, "is using a drug to give people on bed rest more endurance without having to do the exercise."
To which Spiegelman added: "These findings in time may benefit people with Type II diabetes, as the Type I muscle is more responsive to insulin in regulating blood glucose levels. Hence," he concluded, "our findings could have implications for obesity and diabetes."