What makes muscles grow? The obvious answer would be intense exercise and good nutrition, with enough rest and recuperation to maximize size and strength gains. The reason lifting weights produces greater gains in muscle size and strength is that it places more stress on the muscles compared to other types of exercise, such as stretching or aerobics. The muscles respond to the stress through adaptation, involving upgraded muscle protein synthesis.
That’s the general picture of what causes muscle growth. What happens in the muscle after exercise is a much more complex picture. On a molecular level, muscle growth is a precise symphony involving the immune system, inflammation, hormone release and structural changes. While the knowledge of what’s happening in a muscle during and after training may seem superfluous to anyone except a research scientist, a rudimentary understanding of the internal workings of exercised muscles can tell you what constitutes correct training and rest cycles for gains in size and strength.
What Is Muscular Hypertrophy?
The term hypertrophy means “excessive growth,” and in reference to muscles, that means enlarged muscles usually acquired through exercise. An ongoing debate in physiology is whether muscles get bigger through the addition of new fibers—a process called hyperplasia through which existing muscle fibers split to form new fibers—or whether muscles grow by thickening existing fibers. The fiber-thickening scenario is the generally accepted view.
Some studies comparing world-class bodybuilders to untrained college students showed that both groups’ muscle fibers had similar dimensions when viewed under a microscope, though the bodybuilders clearly had much larger muscles. Later studies showed that the bodybuilders had far more muscle fibers than untrained college students. The speculation is that years of intense, heavy training promote hyperplasia of muscle fibers.
Muscle size is related to the cross-sectional area of muscle fibers, or their thickness. As the muscle fiber thickens from a compensation effect induced by heavy exercise, the muscle gets bigger and stronger. Big muscles aren’t always stronger muscles, however. What determines muscle strength is a combination of factors, including favorable leverage and connective tissue. Most important is the increase in muscle contractile proteins, specifically actin and myosin. Some pathological conditions feature large but, paradoxically, weak muscles. An example is acromegaly, usually the result of a small tumor in the anterior pituitary gland that causes the release of huge amounts of growth hormone. People suffering from the disease from an early age wind up very tall, with larger but weaker muscles.
Indeed, the majority of studies examining the athletic use of growth hormone injections conclude that the drug promotes larger muscle size but without an accompanying increase in strength. GH promotes connective tissue increase in muscle but doesn’t affect the muscle contractile proteins that are the cornerstone of muscular strength.
Satellite Cells: The Inner Space of Muscles
Satellite cells are so named because of their location on the outer surface of the muscle fibers, between the muscle cell membrane, or sarcolemma, and uppermost layer of the basement membrane, or basal lamina. Satellite cells are muscle precursors, or a type of stem cell, that usually lie dormant outside existing muscle fibers. They become activated when any form of trauma, such as damage or injury, occurs to a muscle fiber.1 Resistance exercise, as exemplified by weight training, causes damage to muscle fibers, which deal with it by marshaling adaptation mechanisms, the most significant being activation of satellite cells.
The damage causes satellite cells to multiply, and various other factors, as we’ll see, cause them to migrate toward the injured area. The satellite cells then fuse to the injured area, while adding a nucleus to the existing fiber, which aids the regeneration process. That doesn’t add new muscle fibers but instead leads to an increase in the amounts of contractile proteins—the actin and myosin—within the fiber. The net effect is muscular growth and strength. The process peaks at 48 hours but continues for four days after the initial trauma (exercise) occurs. That’s why you need time to let a muscle recover after a training session.
Two main types of muscle fibers are found in humans. The first are known as type 1, or slow-twitch, fibers, also called endurance fibers because of their capacity for extended exercise, such as long-distance running. The other type of muscle fiber, type 2, or fast-twitch, are much larger than the type 1 fibers. They have less endurance but can exert more force, an effect thought to be related to their having a larger nerve supply. Type 2 fibers are most amenable to gains in muscular size and strength, so you’d think they’d have a larger supply of satellite cells around them. In fact, the type 1 fibers have five to six times more, which may reflect their greater blood and capillary supply. (Some studies, however, show an equal number of satellite cells in both types.)
Another reason for the plethora of satellite cells in type 1 fibers is that they’re used more frequently than type 2s. Muscles function through an orderly recruitment system, and the body attempts to husband its limited energy by activating only enough muscle to do the required task. The first fibers recruited are type 1s, and so they’re subject to a greater rate of injury than the type 2s. As type 1 fibers become fatigued or get stressed by mass or weight, the brain recruits the type 2 muscle fibers. That explains why you need to lift heavy to make maximum gains in the gym. Lifting light weights for higher reps recruits the type 1 fibers, which, as noted, are less likely to get bigger and stronger.
Most people over age 40 will tell you that it’s harder for them to make significant gains in muscle size, even with regular training. One reason is a relative lack of testosterone, a hormone required for building muscle. The level of testosterone that physicians call “normal” is okay for everyday life, but having a blood testosterone level lower than 300 makes gains in the gym unlikely at best.
Another reason for the slowdown of muscle gain with age is a loss of neuromuscular efficiency: The muscles become less responsive to the cues from the brain. Without the optimal level of nerve force, a muscle cannot contract as forcefully, and the net effect is a loss of speed, size and strength. Lessened nerve force is usually the reason illustrious athletic careers end. The muscles may still be in relatively good shape, but the response systems are delayed.
Those over 40 also find that it takes longer to recover from training sessions. Connective tissue, such as ligaments and tendons, has a far poorer blood supply than muscles, which is why connective tissue injuries take longer to heal. With age such tissues get dryer, leading to an even longer recuperation time. Since connective tissue plays a role in muscle strength, if you attempt to train too much or too frequently, you won’t make any gains and will feel overtrained.
People 40 and older often have fewer satellite cells than younger people—40 percent less relative to the total number of muscle nuclei. Since you need satellite cells to repair damaged muscle, the significance of the loss is obvious; however, it may not be as extreme in those with a long history of training. One study of powerlifters found that the satellite cell content of their trapezius muscles was 70 percent higher than that of nonexercising subjects. 2 The study also featured powerlifters who were taking anabolic steroids, and their level of satellite cells was similar to that of the “clean” lifters.
Recent studies show that while heavy resistance exercise is the best way to recruit and activate satellite cells, endurance exercise can also increase satellite cell activity. A study of older men involved in endurance exercise without weight training showed that they had a 29 percent increase in satellite cell activity.3 What ultimately determines satellite cell activation is the extent of muscle fiber damage. As you might expect, satellite cell numbers decrease—gradually but regularly—when training ceases. Training enables satellite cells to constantly renew themselves.
What Stimulates Satellite Cells?
Clearly, exercise activates satellite cells. Other factors help maximize the effect. The initial localized inflammation is necessary for containing and repairing the damage, as well as attracting the immune cells, or macrophages, that sweep the area of accumulated muscle waste products. The macrophages secrete cytokines, which are messenger chemicals that signal the release of various growth factors. Cytokines also promote the entry of other immune cells into the area of muscle fiber damage, including lymphocytes, neutrophils and monocytes.
The cytokines involved in muscle repair include interleukin-1, interleukin-6 and tumor necrosis factor. Other initial inflammatory substances that are vital for the process are prostaglandins, which are hormonelike chemicals made from dietary fat. In particular, prostaglandin F2a, derived from arachidonic acid, is pivotal in muscle protein synthesis. The importance of the initial inflammation is illustrated by recent studies showing that when you take an anti-inflammatory drug following training, muscle repair and muscle protein synthesis are inhibited. Fortunately, aging doesn’t seem to have any effect on the prostaglandin response to training.4
The Muscle Growth Factors
Various growth factors and hormones also are directly involved in the repair and anabolic processes within exercised muscle. Some are used in drug form for athletic and bodybuilding purposes.
Insulinlike growth factor 1
IGF-1 is produced both systemically and locally in muscle. It’s a string of amino acids in a specific sequence. Human growth hormone stimulates the production of IGF-1 in the liver, and IGF-1 activity is considered the source of most of the anabolic effects associated with growth hormone.
In muscle, IGF-1 promotes the activity of satellite cells.5 It splits into two variants, the other being mechano growth factor. MGF is considered far more potent than localized IGF-1 in muscle.6 It replenishes the pool of muscle satellite cells, and a lack of MGF explains why older people cannot efficiently activate their satellite cells after exercise. Interestingly, when older men are given growth hormone and then lift weights, their bodies produce increased levels of MGF, leading to muscular gains. The growth hormone does that because it increases IGF-1, which then produces MGF.
Studies of animals injected with MGF show gains of 25 percent in muscle fiber size after only three weeks. In contrast, using gene therapy to deliver IGF-1 genes directly into a muscle resulted in a 15 percent muscle size increase after four months.
Research like that has two implications. The first is that gene therapy involving upgraded local production of IGF-1 or, preferably, MGF dramatically offsets the loss of muscle size and strength common with aging, so it may be of use in treating various neuromuscular disorders. The second is that MGF is a prime candidate for future athletic doping use. Already, rumors published on the Internet indicate that some athletes may be using MGF, although how and whether they actually got a still experimental drug is open to question.
Besides activating satellite cells, IGF-1 sets off so-called downstream growth pathways, such as the Akt, mTOR and P70 signaling pathways, all of which are involved in muscle protein synthesis.7 You may have read recent ads touting products that “turn on the genetic muscle machinery.” They’re based on the idea that oral intake of certain nutrients, such as branched-chain amino acids, can activate downstream growth pathways and overcome age deficits.8
Hepatocyte growth factor
So named because its growth-promoting effects were originally observed in liver tissue, HGF is activated by muscle injury and is a potent stimulant to satellite cell activity. In one study HGF directly injected into the site of muscle injury led to a 300 percent increase in satellite cell activity.9
Its release in injured muscle is instigated by nitric oxide, explaining one way in which NO promotes muscular growth. Inhibiting the release of NO also leads to a blockage of HGF release.
Fibroblast growth factor
FGF increases the proliferation of satellite cells following injury to muscle fibers. Although several FGFs exist, one in particular, FGF-6, is expressed specifically in muscle and is not upregulated during regeneration.11
The Hormonal Effect
Various anabolic hormones, including growth hormone, IGF-1, testosterone and insulin, all play vital roles in promoting muscular size and strength gains.
1) Growth hormone
As noted, most of the anabolic effects of GH are attributed to the
stimulation of IGF-1 promoted by GH release. The IGF-1 produced in
muscle splits into two variants, the more potent being MGF. IGF-1 is
likely the most potent growth factor in relation to satellite cells,
since it’s involved in all three processes of satellite cells:
activation, proliferation and differentiation. Studies show that most of the gains attributed to GH use consist of water retention and connective tissue, with no effect on muscle contractile proteins. On the other hand, GH’s effects in maintaining the integrity and healing ability of connective tissue is beyond debate, which would mean that it’s still useful to athletes. In addition, combining weights with GH appears to increase the selective release of MGF, which is without question anabolic in muscle. MGF is potent enough to restore muscle gains in older people, indicating a use for GH until MGF gene therapy is perfected.
Another thing to consider is that GH appears to promote the use of bodyfat as an energy source while sparing muscle glycogen reserves. That associates it with a beneficial effect on body composition.
2) Testosterone
Test and its synthetic versions (known as anabolic steroids) is the
primary hormone associated with increased muscle size to most people.
Some recent studies show that testosterone directly activates satellite
cells, which explains a large part of its anabolic effect.12 That makes sense, since satellite cells are known to produce androgen receptors, which interact with testosterone.13In animals and humans, testosterone increases the number of satellite cells in muscle. It also interacts with growth hormone and IGF-1, triggering the release of local IGF-1 in muscle. In fact, testosterone appears to make muscle cells more responsive to the effects of IGF-1, which could explain why some athletes stack it with growth hormone and IGF-1.
The importance of testosterone in gaining muscular size and strength is illustrated by a new study.14 Twenty-two young men, all of whom had some minor experience in weight training, were divided into groups. One group got a drug called goserelin (3.6 milligrams), and the other got a placebo. The drug inhibits gonadotropin-releasing hormone in the hypothalamus, which turns off the body’s testosterone production. The subjects got it subcutaneously, or under the skin, every four weeks for 12 weeks. Both groups engaged in strength training for eight weeks.
The drug suppressed both total and free testosterone in the treated group to the extent that the subjects’ testosterone levels were 10 percent below normal. Those in the placebo group—who didn’t get the active drug—made significant gains. Those in the drug group made no gains whatsoever in muscular size and strength. Even worse: They showed an increase in fat mass.
The lack of testosterone in the drug group led to a depression in IGF-1, which in turn led to decreased muscle repair due to satellite cell depression. Testosterone also offsets the effects of cortisol, a catabolic adrenal hormone produced during exercise. Having a metabolic profile that knocks out big T while leaving the effects of cortisol unchecked inevitably leads to no muscle gains coupled with increased bodyfat, especially in the trunk.
Interestingly, two subjects in the drug group showed extreme increases in lean body mass, despite having low testosterone levels. The authors explain the apparent anomaly by noting that the adrenal glands produce 10 percent of androgen in men, and that would not be suppressed by the drug used in the study, which acts only on the pituitary gland to prevent the release of luteinizing hormone. IGF-1, MGF and other muscle growth factors may not have been affected in these particular young men, but they can be considered an exception to the rule, since the study clearly shows that a lack of sufficient testosterone does prevent muscle gains in most people.
The Anti-Growth Factors: Myostatin and Cortisol
Some substances that inhibit muscle growth also play a role in how fast you make gains. The most familiar of them is cortisol.
Cortisol is considered a stress hormone, since any type of stress provides a stimulus for its release from the cortex portion of the adrenal glands. The release of cortisol is governed by a biochemical cascade. First, stress is perceived in the brain in the hypothalamus, which directly interacts with the nervous system. The hypothalamus then releases corticotropin-releasing hormone, which travels in the brain’s portal blood system to the pituitary gland. Upon arrival, CRF stimulates the synthesis and release of ACTH, which then travels in the blood to the adrenal glands, where it dictates the synthesis and release of cortisol.
Cortisol has acquired an unsavory reputation as the body’s primary catabolic hormone. The constant stress of everyday life, including the stress of intense exercise, leads cortisol to have an overkill effect. If the level of cortisol exceeds that of its anabolic opposites GH and testosterone, a catabolic state results, leading to a loss of muscle.
Excess cortisol promotes fat deposition in the trunk, though that is more often seen in pathologic excesses of cortisol, as occurs with Cushing’s disease. In normal instances, cortisol encourages the use of fat as an energy source, particularly after exercise.
Cortisol is also a potent immunosuppressive and anti-inflammatory mediator—most apparent when certain drugs are used that suppress cortisol release. Athletes who resort to such drugs often report severe joint pain, the result of insufficient anti-inflammatory activity.
The good news is that it’s not hard to control cortisol release through nutrition. Just taking in carbs during and after training significantly curtails its catabolic effects. Using a supplement rich in branched-chain amino acids will blunt or prevent them, as will the amino acid glutamine. A recently published study showed that glutamine specifically blocked cortisol’s catabolic effects in muscle by preventing a cortisol-promoted increase in myostatin.15
Myostatin is a protein made up of 375 amino acids.16 It was initially identified by a group at the Johns Hopkins Medical center in Baltimore in 1997. Researchers noticed that mice who lacked the genes to produce myostatin were 30 percent heavier than normal mice, and the extra weight consisted entirely of muscle. That effect was also observed in double-muscled cattle, with the animals having mutations in the myostatin gene that caused them to have huge, defined muscle. In 2004 a report emerged of a human baby born without myostatin genes who was also noticeably stronger and more muscular than other children.
Myostatin does its dirty work in muscles—against IGF-1 and other muscle growth factors—by inhibiting the proliferation and differentiation of satellite cells. Several top pro bodybuilders are said to have mutant genes that make them produce less myostatin than normal. Such people would be far more responsive to training, even without anabolic steroids and other drugs.
Myostatin and cortisol appear to interact, in that they increase each other’s levels. Diseases entailing catabolic states, such as certain forms of cancer and HIV, are characterized by higher levels of both hormones.
Most but not all studies show that weight training lowers myostatin.17, 18, 19 One experiment also showed that the effect was accentuated by the use of a high-quality protein supplement. Excess aerobic exercise (more than 60 minutes in one session) will increase both cortisol and myostatin.
A few years ago some supplement companies attempted to sell a pricey myostatin blocker derived from a type of seaweed. While it did block myostatin in the test tube, further trials showed it to be ineffective in the human body. Subsequently, the researchers who discovered myostatin announced the production of a drug that was effective in the body, promoting a 60 percent increase in animal muscle growth. Another company, Wyeth Pharmacueticals, already has an artificial antibody drug (MYO-029) that blocks myostatin in the human body, intended for the treatment of muscular dystrophy. No doubt the drugs will eventually trickle down into athletic use, and the results should be interesting.
The factors affecting muscle growth and strength gains are complex and not yet fully understood. What is known and accepted, however, is that the long-held rules of bodybuilding—proper nutrition, rest and judicious levels of exercise—will do the most to trigger the internal events that build muscle.
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