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7Muscle Mass and Weight Gain
Nutritional Supplements
Bill Campbell
Abstract
There are numerous sports supplements available that claim to increase lean
body mass. However, for these sports supplements to exert any favorable
changes in lean body mass, they must influence those factors regulating skeletal
muscle hypertrophy (i.e., satellite cell activity, gene transcription, protein
translation). If a given sports supplement does favorably influence one of
these regulatory factors, the result is a positive net protein balance (in which
protein synthesis exceeds protein breakdown). Sports supplement categories
aimed at eliciting a positive net protein balance include anabolic hormone
enhancers, nutrient timing pre- and postexercise workout supplements, antic-
atabolic supplements, and nitric oxide boosters. Of all the sports supplements
available, only a few have been subject to multiple clinical trials with repeated
favorable outcomes relative to increasing lean body mass. This chapter focuses
on these supplements and others that have a sound theoretical rationale in
relation to increasing lean body mass.
Key words
Sports nutrition Lean body mass Creatine Protein supplements HMB
Nitric oxide Anabolic Anticatabolic Nutrient timing
1. INTRODUCTION
To appreciate fully how certain nutritional supplements
increase lean body mass, a thorough understanding of the struc-
tural, systemic, and molecular processes that are responsible for
such increases in lean body mass is needed. Although there is still
a lot to be determined and understood relative to how skeletal
muscle is increased, research scientists for the most part have
From: Nutritional Supplements in Sports and Exercise
Edited by: M. Greenwood, D. Kalman, J. Antonio,
DOI: 10.1007/978-1-59745-231-1_7, ÓHumana Press Inc., Totowa, NJ
189
agreed on several key components that are absolutely necessary
for such adaptations to occur. Some of these components are
satellite cell activity, muscle-specific gene transcription, protein
translation, and nutrient (amino acid) transport into the skeletal
muscle. In addition, growth factors/anabolic hormones including
testosterone, growth hormone, insulin-like growth factor-1
(IGF-1), and insulin are also necessary for increases in skeletal
muscle mass.
Although some sports supplements have been repeatedly
observed to increase skeletal muscle mass, they are at best utilized
as a complement to an optimally periodized resistance training
program. In fact, the greatest stimulus for muscle hypertrophy
is mechanical stress in the form of resistance training. The main
question to ask relative to sports supplements is whether a given
supplement is able to augment the stimulus of resistance training so
muscle hypertrophy is maximized. An overview of how skeletal
muscle hypertrophy is regulated follows.
2. IMPORTANCE OF NET PROTEIN BALANCE
The functional component of skeletal muscle is comprised of
two primary proteins: actin and myosin. Of the two, myosin is
the primary protein that increases in size. Hence, when exercise
biochemists observe changes in muscle mass from a cellular frame
of reference, myosin is often the protein of interest. From a
general perspective, muscle hypertrophy can be summarized by
the status of net protein balance. Net protein balance is equal to
muscle protein synthesis minus muscle protein breakdown. For
skeletal muscle hypertrophy to occur, the net protein balance must
be positive (synthesis must exceed breakdown). At rest, in the
absence of an exercise stimulus and nutrient intake, the net protein
balance is negative (1–4). As previously stated, resistance training
is essential for creating the stimulus necessary for skeletal muscle
hypertrophy to occur. However, when resistance training is per-
formed alone, in the absence of nutritional and supplemental inter-
ventions, net protein balance still does not increase to the point of
becoming anabolic. Specific nutrients and supplements noted later
190 Campbell
in the chapter are needed in conjunction with the resistance training
for the net protein balance to become positive.
3. ROLE OF GENES IN SKELETAL MUSCLE
HYPERTROPHY
As already mentioned, net protein balance has two components:
synthesis and breakdown. To understand how sports supplements
can increase protein synthesis, an understanding of the biochem-
ical process is needed. The center of all bodily functions (including
the addition of skeletal muscle) is at the level of genes. Specific to
hypertrophy, it is the genes that must be expressed as the proteins
in skeletal muscle (i.e., myosin and actin). For instance, once
muscle-specific genes are activated, they are copied into messenger
RNA (mRNA), which is specific to certain proteins in cells. Once
mRNA is transcribed, it is then translated into actual proteins.
Using myosin as an example, what must first happen is an increase
in activation of the myosin gene. Once the myosin gene is acti-
vated, is it copied into myosin mRNA. It is this myosin mRNA
that then directs the process of changing amino acids into poly-
peptides and ultimately a functional myosin protein that is added
to the existing matrix of the sarcomere. The point at which the
myosin protein is synthesized (from the addition of amino acids
under the direction of mRNA), the myosin gene is said to be
‘‘expressed.’’ The reason why all of this tedious biochemical infor-
mation is necessary is that any supplement that claims to increase
muscle mass must in some way influence one of these aforemen-
tioned variables. For instance, some supplements increase growth
hormone, which has been associated with increases in IGF-1. IGF-1,
in turn, increases the activity of certain cell-signaling pathways,
which may increase muscle-specific (i.e., myosin) gene transcrip-
tion. Other sports supplements may increase lean body mass by
increasing the rate at which amino acids are synthesized into
muscle proteins under the direction of mRNA. Yet other sports
supplements may increase the delivery of nutrients (i.e., amino
acids, glucose) to contracting skeletal muscle, which conceivably
results in greater substrate from which lean body mass is acquired.
Each of these mechanisms and the supplements that may enhance
Muscle Mass and Weight Gain Nutritional Supplements 191
these contributions to skeletal muscle hypertrophy are discussed.
Following is a discussion of one of the best and traditional sports
supplements—protein.
4. PROTEIN SUPPLEMENTS
When attempting to increase lean body mass, an essential
component equal to a sound resistance training program is protein
consumption. Not only is protein intake required for skeletal
muscle hypertrophy, protein is also needed to repair damaged
cells and tissue and for a variety of metabolic and hormonal
activities. Protein is the only macronutrient that contains nitrogen.
Given the importance of attaining a positive nitrogen balance,
it is vitally important that protein be ingested on a daily (and
meal-to-meal) basis. When discussing protein as a nutritional
supplement, two main questions arise: 1) How much protein is
required for an individual engaging in resistance training? 2) What
are the types of protein supplements and which are the best
sources of protein?
4.1. Protein Requirements
One of the most controversial subjects in the science of sports
nutrition has been protein intake. The main controversy and
divided opinions have focused on the safety and effectiveness of
protein intake currently recommended by the recommended daily
allowance (RDA). Currently, the RDA for protein in healthy
adults is 0.8 g/kg body weight per day (5). This recommendation
accounts for individual differences in protein metabolism, varia-
tions in the biological value of protein, and nitrogen losses in the
urine and feces. When determining the amount of protein that
needs to be ingested to increase lean body mass, many factors
must be considered, such as protein quality, energy intake, carbo-
hydrate intake, the amount and intensity of the resistance training
program, and the timing of the protein intake. Although 0.8 g/kg/
day may be sufficient to meet the needs of nearly all non-resistance-
trained individuals, it is likely not sufficient to provide substrate
for lean tissue accretion or for the repair of exercise-induced
muscle damage (6,7). In fact, many clinical investigations indicate
192 Campbell
that individuals who engage in physical activity/exercise require
higher levels of protein intake than 0.8 g/kg/day regardless of the
mode of exercise (i.e., endurance, resistance) (8–12) or training state
(i.e., recreational, moderately or well trained) (13–15). So the ques-
tion that remains: How much protein is required for individuals
engaging in resistance training and wanting to increase lean body
mass? General recommendations for individuals who engage in
strength/power exercise range from 1.6 to 2.0 g/kg/day (6,13–16).
A protein intake at these levels help ensure that the net protein
balance remains positive, a prerequisite for skeletal muscle hyper-
trophy to occur.
4.2. Types of Protein Supplement
Although protein can be obtained from whole foods, many resis-
tance trained athletes supplement their diet with protein containing
supplements (e.g., protein powders, meal replacements drinks,
sports bars). Advances in food processing technology have allowed
for the isolation of high quality proteins from both animal and plant
sources. Other reasons for supplementing the diet with protein
supplements include convenience, simplicity, and the fact that pro-
tein supplements also have other benefits, such as a longer shelf life
than whole food sources in addition to being more cost-effective in
many cases.
Ingesting protein at 1.6 to 2.0 g/kg/day is not the only parameter
to consider, however, because it is also important to note that not all
protein is the same. Different types of protein are composed of
varying amounts of amino acids, which serve as the building blocks
of protein. There are approximately 20 amino acids that can be used
to make proteins (Table 1). There are eight essential amino acids
that must be obtained from the diet because the body cannot
synthesize these amino acids. There are also approximately six con-
ditionally essential amino acids that the body has difficulty synthe-
sizing, and therefore individuals are primarily dependent on dietary
sources for these amino acids. The body can easily synthesize the
remaining amino acids, so they are considered nonessential. Not all
protein sources contain the same amounts of amino acids. Protein is
classified as complete or incomplete depending on whether it con-
tains adequate amounts of the essential amino acids. Animal sources
of protein contain all essential amino acids and are therefore
Muscle Mass and Weight Gain Nutritional Supplements 193
complete sources of protein, whereas plant proteins are missing
some of the essential amino acids (i.e., incomplete). Additionally,
there are varying levels of quality of protein depending on the amino
acid profile of the protein. Complete protein sources that contain
larger amounts of essential amino acids generally have higher pro-
tein quality.
4.2.1. WHEY PROTEIN
Four of the most common types of protein found in protein
supplements are whey, casein, soy, and egg (ovalbumin) proteins.
Each of these proteins is a complete protein, and all are classified as
high quality proteins. Whey protein, derived from milk protein, is
currently the most popular source of protein used in nutritional
supplements. Whey proteins are available as whey protein concen-
trates, isolates, and hydrolysates. The primary differences among
these forms are the method of processing and small differences in fat
and lactose content, amino acid profiles, and ability to preserve
glutamine residues. In comparison to other types of protein, whey
protein is digested at a faster rate, has better mixing characteristics,
and is often perceived as a higher quality protein. Research has
indicated that the rapid increase in blood amino acid levels follow-
ing whey protein ingestion stimulates protein synthesis to a greater
degree than casein (17,18). Theoretically, individuals who consume
Table 1
Classification of Amino Acids
Essential amino acids
Conditionally essential
amino acids
Nonessential
amino acids
Isoleucine
a
Arginine Alanine
Leucine
a
Cysteine (cystine) Asparagine
Lysine Glutamine Aspartic acid
Methionine Histidine Glutamic acid
Phenylalanine Proline Glycine
Threonine Tyrosine Serine
Tryptophan
Valine
a
a
Branched-chain amino acids
194 Campbell
whey protein frequently throughout the day may optimize protein
synthesis. In fact, a study by Dangin and associates (19) reported
that frequent ingestion of a small amount of whey protein served to
increase protein synthesis to a greater degree than less frequent inges-
tion of various proteins. Overall, whey protein is an excellent source
of protein to supplement due to its amino acid content (including high
branched-chain amino acid content) and its ability to be rapidly
absorbed (20).
4.2.2. CASEIN PROTEIN
Casein, also a milk protein, is often described as a slower-acting
protein (17,19). It is considered a slower protein than whey protein
because it takes longer to digest and absorb. This is most likely due
to fact that casein has a longer transit time in the stomach (17).
Although casein stimulates protein synthesis, it does it to a much
lesser extent than whey protein (17). Unlike whey, casein helps
decrease protein breakdown (21), which has led to the status of
casein as having anticatabolic properties. Given the findings that
whey protein stimulates protein synthesis and casein helps decrease
muscle breakdown, some supplement manufacturers add both whey
and casein to their formulations. The effectiveness of combining
whey and casein proteins was illustrated in a recent investigation
conducted by Kerksick and colleagues (22). In their study, subjects
performed a split body part (training the upper body on one day and
the lower body on another) resistance training program 4 days a
week for 10 weeks. The subjects were given 48 g of carbohydrate or
40 g of whey þ8 g of casein or 40 g of whey þ5 g of glutamine þ3g
of branched-chain amino acids (BCAAs). After 10 weeks, the group
supplemented with combined whey and casein had the largest
increase in lean muscle mass.
4.2.3. SOY PROTEIN
Although soy lacks the essential amino acid methionine, it has a
relatively high concentration of remaining essential amino acids and
is therefore considered a high quality protein. Soy protein is made
from soybeans using water or a water–ethanol mixture to extract
the protein (20). Soy protein is similar to whey protein in that there
is a soy protein concentrate and isolate. Soy contains compounds
called isoflavones, which appear to be strong antioxidants and
have been implicated in possibly decreasing the risk of developing
Muscle Mass and Weight Gain Nutritional Supplements 195
cardiovascular disease and cancer. In addition to isoflavones, soy
proteins contain protease inhibitors. Given these attributes of soy,
there is some evidence to suggest that soy may decrease or prevent
the exercise-induced damage to muscle seen following a workout
(23). At this point, there are few data relative to soy protein inges-
tion and accretion of lean body mass in conjunction with resistance
training; therefore, more research is needed before definitive recom-
mendations can be given.
4.2.4. EGG PROTEIN
Egg protein is also a high quality protein and has the advantage
of being a miscible protein (it mixes easily in solution) (20). How-
ever, egg protein supplements generally do not taste good and are
more expensive than other protein supplements. For these reasons,
along with the availability of other high quality proteins such as
whey, casein, and soy, egg protein supplementation is not popular
among athletes. Despite this, egg protein is still added in small
quantities to some meal replacement/protein powders (20).
4.3. Summary
Adequate protein intake consisting of high quality proteins is a
prerequisite for the accretion of lean body mass stimulated by a
proper resistance training program. Whey, casein, soy, and egg
proteins are all high quality proteins and are commonly found in
protein supplements marketed to strength-trained athletes. In addi-
tion to ingesting the proper amounts and quality of proteins, the
timing of protein intake has been a recent area of scientific investi-
gation. A discussion of the importance of this concept, known as
‘‘nutrient timing,’’ follows.
5. CARBOHYDRATE–PROTEIN COMBINATIONS
Ingestion of a high quality protein is essential for increasing lean
body mass, but equally important is the timing of the protein
intake. This category of sports nutrition has been categorized as
nutrient timing, and there are multiple research studies highlighting
the importance of appropriately timing certain meals throughout
theday.Insummary,thecentralideaunderlyingnutrienttiming
is to time high glycemic carbohydrate and protein ingestion so
196 Campbell
it encompasses the time frame in which the resistance training
bout exerts a hypertrophic stimulus on the trained skeletal muscles.
More specifically, stimulated myofibers are ‘‘primed’’ to synthesize
protein, but both insulin and amino acid substrate are required to
maximize this adaptation in the moments following an acute bout of
resistance exercise. This time period following a resistance training
session is commonly referred to as the anabolic window to emphasize
that this time frame has specific anabolic potential.
5.1. Resistance Training in the Absence of Nutritional Intake
Inherent with the term anabolic window is the concept of net
protein balance. As stated earlier, net protein balance is equal to
muscle protein synthesis minus muscle protein breakdown. For
skeletal muscle hypertrophy to occur, net protein balance must be
positive (synthesis must exceed breakdown). To improve net protein
balance, an appropriate stimulus (e.g., resistance training) must be
applied to the skeletal muscles. However, when resistance training
is performed alone, in the absence of nutritional and supplemental
(i.e., protein, carbohydrate) interventions, net protein balance
still does not increase to the point of becoming anabolic. Several
studies observing the effects of resistance training and acute changes
in net protein balance have concluded that net protein balance is
improved as a result of the resistance training bout. Although
resistance exercise improves the net balance by stimulating muscle
protein synthesis, however, nutrient intake is required for the synth-
esis to exceed the breakdown (24).
As support for this contention, Biolo and colleagues (1) assessed
rates of protein synthesis and degradation at rest and 3 hours after a
resistance training routine in fasted subjects. At 3 hours after exer-
cise, protein synthesis had increased approximately 108% and pro-
tein breakdown had increased 51%. Thus, resistance exercise
improved the net protein balance by increasing protein synthesis at
a greater rate than protein breakdown. Although the net protein
balance was improved, it is important to note that it did not improve
to the point of becoming positive (anabolic).
Phillips and coworkers (3) conducted a similar study in which
they recruited two groups of participants (resistance trained and
untrained) and had them perform an eccentric-only resistance
exercise workout in a fasted state. Rates of protein synthesis and
Muscle Mass and Weight Gain Nutritional Supplements 197
breakdown were measured within 4 hours of completing the resis-
tance training protocol. Following the resistance training bout,
muscle protein synthesis rates increased by 118% in the untrained
group and by 48% in the resistance trained group. In terms of
muscle protein breakdown, there was an increase of 37% in the
untrained group and an increase of 15% in the resistance-trained
group. Relative to the net protein balance, the resistance training
protocol significantly improved this measure in both groups (þ37%
in the untrained group and þ34% in the trained group), but the
overall net protein balance was still negative following the bout of
resistance training.
Using a larger time frame, this same researcher (2) assessed rates
of protein synthesis and protein breakdown at rest and at 3, 24, and
48 hours after a resistance training workout in recreationally active
(but not previously resistance trained) subjects. Unfortunately,
however, the net protein balance was not assessed in the fasted
state; rather, each participant ingested food at his own discretion.
There was an important nutritional restriction employed: The par-
ticipants were instructed to eat a meat-free diet during the study
(which limited protein intake). In addition, it appears that the
3-hour net protein balance assessment was conducted in the fasted
state. Muscle protein synthesis was significantly increased at each
time point following the resistance training bout: at 3 hours 112%;
at 24 hours 65%; at 48 hours 34%. Muscle protein breakdown was
also increased by 31% at 3 hours after exercise and by 18% at
24 hours. Muscle protein breakdown returned to resting levels by
48 hours. One of the novel findings of this study was the observation
that muscle protein synthesis was elevated (by 34%) 48 hours after
exercise, during which time muscle protein breakdown returned to
baseline levels. Despite this finding, at no time point did the net
protein balance become positive (likely due to the restrictions on
protein intake).
In summary, each of these aforementioned studies indicates that
resistance training alone is not enough to elicit positive changes in
net protein balance that lead to increases in lean body mass.
5.2. Insulin, Amino Acids, and Protein Synthesis
As stated in the introduction to the chapter, muscle-specific genes
must be activated to initiate the process of skeletal muscle
198 Campbell
hypertrophy. Once these muscle-specific genes are activated, they
are copied into messenger RNA (mRNA) which serves as a template
for which muscle proteins are then manufactured (translated).
Many researchers believe that resistance training acts as the stimu-
lus for activating muscle-specific genes, but once these genes are
copied into muscle-specific mRNA transcripts still other factors
are needed to convert the muscle-specific mRNA into functional
skeletal muscle proteins. Two biological compounds have been
shown to be an integral part of this process: insulin and amino
acids. In fact, Bolster and coworkers (25) stated in a review paper
that, ‘‘Without question, investigating the singular role of amino
acids or insulin in promoting changes in skeletal muscle protein
synthesis with resistance exercise is crucial to elucidating mechan-
isms regulating muscle hypertrophy.’’
Insulin has several roles relative to improving the net protein
balance following resistance exercise, including increasing protein
synthesis (26–28), improving the transport of amino acids into
skeletal muscle (27,29,30), and decreasing protein breakdown
(30–33). Whereas insulin should never be injected (as multiple
adverse events are likely to occur) for the purposes of improving
net protein balance, insulin can be significantly increased endogen-
ously via the consumption of carbohydrate. As important as insulin
concentrations are to anabolic processes, Biolo and Wolfe (34)
stated that if high levels of insulin are not supported by an exogen-
ous amino acid supply, insulin loses its anabolic capacity in skeletal
muscle. This observation has been shared by other investigators as
well (35,36).
Relative to protein synthesis, when essential amino acids were
ingested after a bout of resistance exercise, the net protein balance
was changed from a negative to a positive state (37). Other clinical
studies have also demonstrated that the oral ingestion of amino
acids are responsible for increasing protein synthesis rates in multi-
ple populations of participants (38,39). Given the importance of
insulin and amino acid availability relative to improving net pro-
tein balance, ingesting these nutrients simultaneously is recom-
mended. To further this recommendation, by adding a protein
source to carbohydrate ingestion it is possible to increase insulin
to levels higher than those induced by carbohydrate ingestion
alone.
Muscle Mass and Weight Gain Nutritional Supplements 199
5.3. Importance of Combined Carbohydrate–Protein
Supplements and Timing of Ingestion
Carbohydrate (to elevate insulin) and amino acids are needed to
maximize positive shifts in net protein balance, and the time course
for which they must be present should be considered. To highlight
the importance of timing, note that when 10 g of protein, 8 g of
carbohydrate, and 3 g of fat were ingested either immediately or
3 hours after exercise, protein synthesis was increased more than
threefold with the supplement ingested immediately versus ingestion
3 hours after exercise (with which there was only a 12% increase)
(40). In a study by Rasmussen and coworkers (41), subjects were
given an amino acid–carbohydrate drink or a placebo following a
resistance exercise session. Not surprisingly, the amino acid–carbo-
hydrate drink elicited an anabolic response compared to the pla-
cebo. In another study of protein breakdown, Bird and colleagues
(42) gave subjects one of four supplements after a bout of resistance
exercise: 1) carbohydrate beverage; 2) essential amino acids; 3)
combination of carbohydrate and amino acids; 4) placebo. The
result of this nutritional intervention revealed that protein degrada-
tion (as measured by urinary 3-methylhistidine) was elevated at 24
and 48 hours after exercise in the placebo group. Relative to the
carbohydrate and amino acid group, protein degradation was
unchanged at 24 hours and actually decreased 48 hours after exer-
cise. Given these findings and the data on the aforementioned
studies, properly timed carbohydrate–protein/amino acid supple-
ments not only increase protein synthesis but also seem to attenuate
protein degradation. Most of the scientific investigations have
looked at carbohydrate–protein supplements during the postresis-
tance exercise period; however, one study looked at the difference of
ingesting an amino acid–carbohydrate supplement before versus
after resistance training (43). The investigators reported that pro-
tein synthesis was greater as a result of the preresistance training
intake of the amino acid–carbohydrate supplement, most likely due
to increased delivery of amino acids to the stimulated skeletal muscle
fibers (43).
Most studies have examined the combination of amino acid–
carbohydrate supplements in the time frame that encompasses a
resistance training session, but not many have investigated intact
protein (e.g., whey, casein) supplementation after resistance exercise
200 Campbell
and their effects on the net protein balance. Tipton et al. (44)
studied the ingestion of casein and whey proteins and their effects
on muscle anabolism after resistance exercise. They concluded that
the ingestion of both proteins (whey and casein) after resistance
exercise resulted in similar increases in muscle protein net balance,
resulting in net muscle protein synthesis, despite different patterns of
blood amino acid responses (a quicker response of blood amino
acids for the whey protein and a more sustained response for the
casein protein). In a similar study, Tipton and coworkers (45)
questioned if ingestion of whole proteins before exercise would
stimulate a superior response to that with ingestion after exercise.
The authors reported that the net amino acid balance switched from
negative to positive following ingestion of the whey proteins at both
time points. In another study, when whey protein was added to
an amino acid–carbohydrate supplement, the authors indicated
that there seemed to be an extension of the anabolic effect compared
to that seen with amino acid–carbohydrate supplements without
additional whey protein (46).
5.4. Summary
A proper postworkout supplement designed to increase lean
body mass should contain both carbohydrates and protein and be
in a liquid form. The reason these carbohydrate–protein supple-
ments should be in liquid form is that liquid meals are more pala-
table and digestible. In addition, liquid meals have a fast absorption
profile compared to that of whole foods, which allows faster insulin
secretion and peak plasma amino acid levels—both of which are
essential to take advantage of the anabolic window created by
the resistance training session. This section has highlighted some
of the clinical investigations and the mechanisms as to how appro-
priately timed ingestion of carbohydrate–protein supplements exert
their effects. A more detailed explanation can be found by reading
Chapter 13, on dietary meal and nutrient timing.
6. CREATINE
The sports supplement creatine has been the gold standard
against which other nutritional supplements are compared. The
reason for this prominent position is that creatine improves
Muscle Mass and Weight Gain Nutritional Supplements 201
performance, increases lean body mass, and has repeatedly been
shown to be safe when recommended dosages are consumed. Con-
sequently, creatine has become one of the most popular nutritional
supplements marketed to athletes over the past decade and a half. In
fact, one of the most consistent side effects of creatine supplementa-
tion has been weight gain in the form of lean body mass. This
increase has been observed in several cohorts including males,
females, and the elderly (47–54).
In most of the studies published on creatine supplementation, the
typical dosage pattern was divided into two phases: a loading phase
and a maintenance phase. A typical loading phase consists of ingest-
ing 20 g of creatine (or 0.3 g/kg body weight) in divided doses four
times per day for 2 to 7 days, followed by a maintenance dose of 2 to
5 g daily (or 0.03 g/kg) for several weeks to months at a time (55).
Another consideration relative to creatine dosage is to base the
amount on an individual’s lean body mass. Burke and coworkers
(56) studied this aspect of creatine supplementation by having
subjects ingest creatine at a dosage of 0.1 g/kg of lean body mass
(this equates to approximately 8 g of creatine for a 200 pound indivi-
dual at 15% body fat). Hultman and colleagues (57) demonstrated
another interesting approach to creatine ingestion. They demon-
stratedthatwhencreatinewasingestedat3g/dayoveranextended
training period of at least 4 weeks the skeletal muscle creatine levels
rose more slowly, eventually reaching levels similar to those achieved
with the loading method.
In summary, a quick way to ‘‘creatine load’’ skeletal muscle
requires ingesting 20 g of creatine monohydrate daily for 6 days
and then switching to a reduced dosage of 2 g/day (57). If the
immediacy of ‘‘loading’’ is not an important consideration, supple-
menting with 3 g/day for 28 days achieves the same high levels of
intramuscular creatine (57).
6.1. Effects on Lean Body Mass
What type of weight gain (in the form of lean body mass) can be
expected with this level of creatine supplementation? Many of the
studies performed to date indicate that short-term creatine supple-
mentation increases total body mass by approximately 0.7 to 1.6 kg
(1.5–3.5 lb) (16). Longer-term creatine supplementation (6–8
weeks) in conjunction with resistance training has been shown to
202 Campbell
increase lean body mass by approximately 2.8 to 3.2 kg (7 lb)
(58–60). Gain in lean body mass has also been observed in women
as a result of creatine supplementation. Vandenberghe et al. (47)
investigated the changes in fat-free mass in females who ingested
creatine (20 g/day for the first 4 days followed by 5 g/day for 65 days)
in combination with resistance exercise for 10 weeks. The authors
reported an increase of 5.7 lb of fat-free mass after 10 weeks of
creatine supplementation and resistance exercise. This increase was
60% greater than in the creatine supplementation group compared
to the placebo group.
6.2. Physiological Mechanisms for Increasing Lean Body Mass
The exact physiological mechanisms responsible for increasing
lean body mass as a result of creatine supplementation remain
poorly understood. Early studies investigating creatine supplemen-
tation and weight gain led many to the conclusion that increases in
body weight were due to water retention. However, several more
recent studies suggest that creatine supplementation may help build
lean tissue. Volek et al. (61) reported that during a 12 week resis-
tance training program, resistance trained males ingesting creatine
significantly increased the fat-free mass compared to those ingesting
a placebo. Furthermore, it was reported that the subjects given
creatine demonstrated significantly greater increases in types I
(35% vs. 11%), IIA (36% vs. 15%), and IIAB (35% vs. 6%) muscle
fiber cross-sectional areas (61). The percentage increases in cross-
sectional area for all fiber types in those subjects ingesting creatine
ranged from 29% to 35%—more than twice the increase observed in
placebo subjects (6%–15%) (16).
To help elucidate the physiological mechanisms further,
Willoughby and Rosene (62,63) conducted a series of studies inves-
tigating the effects of oral creatine ingestion and the factors involved
in gene expression of contractile filaments and myosin heavy-chain
protein expression. In the first of these studies, untrained male
subjects ingested creatine at 6 g/day or a placebo in conjunction
with heavy resistance training for 12 weeks. At the end of the
intervention, those ingesting creatine significantly increased their
fat-free mass (7 lb) in comparison with the placebo group
(1 lb). One of the most interesting parameters in this study was
the information that was gathered relative to what was occurring at
Muscle Mass and Weight Gain Nutritional Supplements 203
the cellular level of the skeletal muscle. Myofibrillar protein content
(a marker of the amount of intracellular protein) was found to be
significantly greater in the creatine group than in the placebo group
despite the fact that both groups performed identical resistance
training programs. More specifically, the authors reported that
there were significant increases in the content of two isoforms of
myosin heavy-chain protein (the major constituent of contractile
skeletal muscle) (62).
In their other study, Willoughby and Rosene (63) investigated
the effects of ingesting creatine (in conjunction with a resistance
training program) on myogenic regulatory factor gene expression.
Myogenic regulatory factors (which include Myo-D, myogenin,
MRF-4, and Myf5) are proteins that function as transcription acti-
vators that regulate gene expression via their binding to DNA,
ultimately activating the transcription of muscle-specific genes
such as myosin heavy chain, myosin light chain, a-actin, troponin-
I, and creatine kinase (64). After 12 weeks of resistance training, the
authors reported that the subjects ingesting creatine had signifi-
cantly greater mRNA expression for myogenin and MRF-4 than
the subjects ingesting a placebo. These findings provide an insight
into the mechanisms by which creatine supplementation exerts its
effects on increasing lean body mass. Taken together, the aforemen-
tioned studies seem to indicate that the increases in lean body mass
as a result of creatine supplementation are due to augmenting
skeletal muscle fiber hypertrophy and not solely water retention.
6.3. Satellite Cell Activity
In addition to increasing muscle fiber cross-sectional areas,
myogenic regulatory factors, and specific isoforms of myosin
heavy chain, creatine supplementation has been shown to augment
an increase in satellite cell number in human skeletal muscle
induced by strength training. In addition to muscle-specific tran-
scription and translation, activation of satellite cells is thought
to be a major contributing factor to augmenting skeletal muscle
hypertrophy. During the process of load-induced muscle hypertro-
phy, satellite cells are thought to proliferate, differentiate, and then
fuse with existing myofibers (65). The way in which satellite cells
are thought to be involved in skeletal muscle hypertrophy is sum-
marized in what is termed the myonuclear domain theory. This
204 Campbell
theory suggests that the myonucleus controls the production of
mRNA (i.e., transcription) and proteins (i.e., translation) for a
finite volume of cytoplasm, such that increases in fiber size must
be associated with a proportional increase in myonuclei, which are
contributed from the satellite cell populations (66). If this theory
is correct, anything that increases satellite cell activity leading to
increases in myonuclei sets the stage for increased skeletal muscle
hypertrophy.
In a truly original investigation, Olsen and coworkers (67) inves-
tigated the influence of creatine and protein supplementation on
satellite cell frequency and the number of myonuclei in human
skeletal muscle during 16 weeks of resistance training. After the 16
weeks of training, all groups in the clinical trial (creatine, protein,
and placebo groups) demonstrated significant increases in the pro-
portion of satellite cells. However, only the creatine-supplemented
group demonstrated consistent significant increases of myonuclei
per fiber. This finding led the authors to conclude that ‘‘creatine
supplementation in combination with strength training amplifies the
training-induced increase in satellite cell number and myonuclei
concentration in human skeletal muscle fibers, thereby allowing an
enhanced muscle fiber growth in response to strength training’’
(67). Given this important finding relative to creatine supplementa-
tion and satellite cell activity, additional clinical trials investigating
this aspect of creatine supplementation are needed.
7. ANABOLIC HORMONE ENHANCERS
Insulin, growth hormone, testosterone, and insulin-like growth
factor-1 (IGF-1) are all considered primary anabolic hormones. We
have already discussed insulin and its role in translating muscle-
specific mRNA into skeletal muscle proteins, and the effects that
carbohydrate–amino acid supplements have on increasing insulin
levels. The other three anabolic hormones are believed to exert their
effects on the cell-signaling properties of skeletal muscle fibers, which
ultimately result in muscle-specific gene expression. IGF-1, however,
not only acts in this regard (cell signaling) but also acts similarly to
insulin in its role of translating muscle-specific mRNA transcripts
into functional skeletal muscle proteins (actin, myosin). A further
discussion of IGF-1, growth hormone, and testosterone follows.
Muscle Mass and Weight Gain Nutritional Supplements 205
7.1. Insulin-Like Growth Factor-1
There are three isoforms of IGF-1 in human muscle (68): IGF-
1Ea (similar to the type of IGF-1 synthesized in the liver); IGF-1 Eb;
and IGF-1Ec (known as mechano growth factor) (68). IGF-1 is
produced primarily by the liver as an endocrine hormone and
is stimulated by growth hormone release. One of the isoforms of
IGF-1, known as mechano growth factor, is detectable only after
mechanical stimulation (e.g., resistance training). Skeletal muscle
hypertrophy is regulated by at least three major molecular pro-
cesses: 1) satellite cell activity; 2) gene transcription; and 3) protein
translation. Interestingly, IGF-I can influence the activity of all of
these mechanisms (69). That being the case, any increases in IGF-1
could significantly increase the potential for skeletal muscle
hypertrophy.
In addition to growth hormone release and mechanical stimu-
lation, are there any nutritional or supplemental means that
increase endogenous levels of IGF-1? For the most part, the
answer is no, but two studies have reported that supplementation
with bovine colostrum resulted in increases in serum IGF-I con-
centration in athletes during training (70,71). However, owing to
the relatively acute duration of these studies, lean body mass
indices were not measured. Another study that did measure mus-
cle protein balance and strength after 2 weeks of bovine colostrum
supplementation (72) found that the bovine colostrum had no
effect on either of these variables. Given these findings, at this
point it is safe to say that there are no sports supplements that
effectively increase endogenous IGF-1 levels resulting in changes
in lean body mass.
7.2. Growth Hormone
A quick survey of the literature on growth hormone reveals
that the hormone does indeed improve body composition by
simultaneously increasing lean body mass and decreasing body
fat in diseased populations (73–75).However,whatisoftennot
mentioned in the marketing campaigns of sports supplements
designed to increase growth hormone is the fact that most of
these clinical investigations introduced growth hormone into
their subjects via subcutaneous injection. Many sports supple-
ments designed to increase endogenous levels of growth hormone
206 Campbell
are based on studies showing that specific amino acids are able
(inconsistently) to increase growth hormone. The main amino acid
that has demonstrated potential to increase growth hormone is
arginine. As discussed below, arginine is often combined with
other compounds to elicit growth hormone release.
It is well documented that the infusion of arginine stimulates
growth hormone secretion from the anterior pituitary (76,77).
This increase in growth hormone secretion from arginine infusion
has been attributed to the suppression of endogenous somatostatin
secretion (76). The amounts of arginine infused to elicit the growth
hormone response ranged from 12 to 30 g. The clinical investiga-
tions observing oral consumption of arginine and its impact on
growth hormone release are equivocal. Relative to the practical
oral ingestion of arginine, several studies have shown that such
supplementation resulted in significant increases in growth hormone
secretion.
One such study (78) found that oral arginine supplementation of
5 and 9 g resulted in significant growth hormone response in males.
Interestingly, 13 g of oral arginine did not increase growth hormone
levels and caused gastrointestinal distress in most of the subjects. A
common supplemental regimen that has shown promise as a growth
hormone enhancer includes the addition of lysine to arginine. Uti-
lizing this combination, Isidori and colleagues (79) provided 1.2 g
of arginine (as arginine-2-pyrrolidone-5-carboxylate) and 1.2 g of
lysine (as lysine hydrochloride) to young males. Plasma growth
hormone concentrations increased eightfold at 90 minutes after
ingestion. Similarly, Suminski and associates (80) reported that
the ingestion of arginine and lysine resulted in a 2.7-fold increase
in plasma growth hormone concentrations in resistance trained
males.
Another compound commonly added to arginine for the purpose
of eliciting an increase in growth hormone is aspartate. Besset and
colleagues (81) gave male subjects arginine aspartate at a dose of
250 mg/kg/day (approximately 17.5 g of arginine aspartate for a
70 kg male) for 1 week. The results indicated that the sleep-related
growth hormone peak was about 60% higher after a week of argi-
nine aspartate administration than in the controls. Colombani
et al. (82) gave 20 male endurance trained athletes 15 g of arginine
aspartate (7.5 g in the morning and 7.5g in the evening) for 14 days
Muscle Mass and Weight Gain Nutritional Supplements 207
before a marathon run. After 31km had been completed by the
runners, plasma growth hormone levels were 40% greater in the
arginine aspartate group. At the end of the marathon, plasma growth
hormone levels were 8% greater in the supplemented group than in
the placebo group.
Not all studies investigating arginine supplementation and
growth hormone responses have been favorable. Walberg-Rankin
(83) gave resistance-trained males ingesting a hypocaloric diet argi-
nine hydrochloride 100 mg/kg/day (approximately 8 g arginine
hydrochloride) for a 10-day period. This supplementation protocol
did not result in an increase in growth hormone concentration.
Another study also reported no increase in plasma growth hormone
concentrations when elderly men ingested 3 g of arginine and 3 g
lysine for 14 days (84). In yet another study investigating arginine
and growth hormone responses, Marcell et al. (85) investigated
whether oral arginine (5 g) increases growth hormone secretion in
young and old people (male and female) at rest and during resistive
exercise. The authors concluded that oral arginine supplementation
does not increase growth hormone secretion at rest or in combina-
tion with resistive exercise.
There are several reasons for the conflicting results in terms of
arginine eliciting an increase in growth hormone production. Some
of these reasons could be the type of arginine complex, dosages, and
delivery methods used and variations in the subjects themselves. It
has also been suggested that the growth hormone response to amino
acid ingestion may be reduced in individuals who are exercise
trained (55).
Even if certain amino acids do increase growth hormone levels
(a statement not supported by all investigations), it does not
necessarily lead to the conclusion that they increase lean body
mass. In a scientific review on this subject, Chromiak and Antonio
(55) stated: ‘‘There is no evidence based on properly conducted,
rigorous scientific studies that oral supplementation of specific
amino acids induces growth hormone that, in conjunction with
resistance training, increases muscle mass and strength to a
greater extent than resistance training alone.’’ At this point, it
appears as if specific amino acids, even if they do elicit an increase
in growth hormone, do not increase lean body mass via this
mechanism.
208 Campbell
7.3. Testosterone
Although each of the anabolic hormones (testosterone, growth
hormone, insulin, IGF-1) is required to stimulate maximum levels
of skeletal muscle hypertrophy, testosterone may be the most ana-
bolic. It is important to recognize that not all of the testosterone in
the blood is bioavailable; rather, most of it is bound to proteins
such as sex hormone-binding globulin (SHBG) or other carrier
proteins. Testosterone that is not bound is referred to as ‘‘free’’ or
‘‘bioavailable’’ testosterone; and it is able to bind to the androgen
receptor and exert its anabolic signaling. This is an important
distinction because as one attempts to increase testosterone levels
(via testosterone-enhancing supplements) in the body, it is only the
bioavailable testosterone that exerts anabolic actions. Another
important consideration is the avoidance of increasing SHBG to
a greater extent than total testosterone increases, which would
result in an environment in which there is less bioavailable testos-
terone present. Therefore, when investigating sports supplements
designed to increase testosterone, each of these factors must be
considered. Currently, there are a few sports supplements that
claim to increase testosterone levels: ZMA, Tribulus terrestris,
and aromatase inhibitors.
7.3.1. ZMA
The primary ingredients in ZMA supplements are zinc mono-
methionine aspartate, magnesium aspartate, and vitamin B
6
. Zinc
and magnesium deficiencies as well as urine and sweat losses of these
minerals have been observed in athletes and individuals who are
physically active (86–90). Relative to testosterone, there have been
two well designed studies investigating the effects of ZMA supple-
mentation and its effects on testosterone levels, with the studies
reporting contradictory results (91,92).
The first of these studies gave collegiate football players ZMA
(30 mg zinc monomethionine aspartate þ450 mg magnesium aspar-
tate þ10.5 mg of vitamin B
6
) over the course of their spring practice
season (approximately 8 weeks) (91). Total testosterone and, more
importantly, free testosterone were significantly elevated as a result
of the ZMA supplementation compared to that of the placebo
group. This study is consistently cited as proof of the effectiveness
of ZMA to elevate testosterone levels. In the other study (92),
Muscle Mass and Weight Gain Nutritional Supplements 209
researchers gave resistance trained males a ZMA supplement (main
ingredients consisting of 30 mg zinc monomethionine aspartate þ
450 mg magnesium aspartate þand 11 mg of vitamin B
6
) and found
no such increases in either total or free testosterone. This investiga-
tion (92) also assessed changes in the fat-free mass and several
strength and performance variables. No significant differences
were observed in relation to these variables in subjects taking
ZMA. The discrepancies concerning these two studies may be
explained by deficiencies of these minerals. Given the role that zinc
deficiency plays relative to androgen metabolism and interaction
with steroid receptors (93), when there are deficiencies of this
mineral, testosterone production may suffer. In the study showing
increases in testosterone levels (91), there were observed depletions
of both zinc and magnesium in the placebo group over the course of
the study. Therefore, the increased testosterone levels could have
been attributed to impaired nutritional status rather than a pharma-
cological effect. Obviously, more research is needed on supplemen-
tal ZMA before any concrete recommendations can be made
relative to testosterone responses.
7.3.2. TRIBULUS TERRESTRIS
Tribulus terrestris is often marketed as a testosterone-boosting
sports supplement. There are relatively few, if any, scientific studies
to substantiate these claims. In fact, one clinical investigation
demonstrated that Tribulus terrestris exerts no effect on increasing
testosterone levels (94). In this study, healthy men were instructed
to supplement with Tribulus terrestris for a 4-week period after
which serum levels of testosterone and luteinizing hormone were
measured at 1, 3, 10, 17, and 24 days after supplementation. Tribulus
terrestris supplementation did not increase the levels of either tes-
tosterone or luteinizing hormone. Given the unsubstantiated claims
of Tribulus terrestris relative to increasing testosterone levels, sup-
plemental Tribulus is not recommended.
7.3.3. AROMATASE INHIBITORS
Aromatase inhibitors exert their effects by inhibiting the action
of the enzyme aromatase, which converts androgens to estrogens by a
process called aromatization. Aromatase inhibitorsupplements claim
to suppress estrogen levels and increase endogenous testosterone
210 Campbell
levels. In the only published study investigating aromatase inhi-
bitor supplements, Willoughby and colleagues (95) instructed
their male subjects to ingest an aromatase inhibitor supplement
(containing hydroxyandrost-4-ene-6,17 dioxo-3-THP ether and
3,17-diketo-androst-1,4,6-triene) at 72 mg/day for an 8-week per-
iod. At the end of the 8 weeks there was a 3-week washout period.
Multiple anabolic hormones were assayed during the duration
of the study, including total testosterone and free testosterone.
In addition, body composition was assessed during the investiga-
tion in which the participants were instructed to maintain their
normal resistance training programs. There were significant
increases in both total and free testosterone levels compared to
those with placebos, with the total testosterone having an average
increase of 283% and free testosterone an average of 625%. The
aromatase inhibitor supplement had also elicited a 3.5% decrease
in fat mass in the aromatase inhibitor group at the end of the
8-week period. After the 3-week washout period, total and free
testosterone levels decreased to the presupplementation values.
Finally, the aforementioned supplementation appeared to be safe
and well tolerated by the study participants as measured by blood
and urinary clinical safety markers. Although this study appears
to support aromatase inhibitor supplementation for the purpose
of increasing endogenous testosterone levels, additional studies
are needed to replicate these findings. In summary, it appears that
of all the nutritional supplements designed to increase testoster-
one levels aromatase inhibitor supplementation is the most scien-
tifically valid option.
8. ANTICATABOLIC SUPPLEMENTS
Because the net protein balance is equal to muscle protein synthesis
minus muscle protein breakdown, eliciting increases in lean body
mass can be achieved not only by increasing protein synthesis but
also by decreasing protein breakdown (catabolism). Hence, a number
of sports supplements are marketed for that endeavor, including
glutamine, cortisol inhibitors, b-hydroxyl-b-methylbutyrate (HMB),
and a-ketoisocaproic acid. In addition to these specific sports
supplements, insulin has been shown repeatedly to suppress protein
Muscle Mass and Weight Gain Nutritional Supplements 211
breakdown (30,31,96,97). Hence, carbohydrate (or carbohydrate þ
protein) taken after resistance exercise (a period when protein break-
down is elevated) for the purpose of increasing insulin secretion is a
recommended practice to suppress protein breakdown (42).Other
purported anticatabolic supplements are discussed below.
8.1. a-Ketoisocaproic Acid
a-Ketoisocaproic acid (KIC) is the keto acid of the BCAA
leucine. Despite many claims of KIC and its anticatabolic proper-
ties, there is only one peer-reviewed study in humans that has
investigated the inclusion of KIC (along with HMB) on a specific
marker of muscle damage (creatine kinase). When non-resistance-
trained males ingested 3 g of HMB and 0.3 g of KIC daily for
14 days prior to a resistance training session, it was reported that
the HMB–KIC supplementation attenuated the creatine kinase
response compared to that seen with the placebo (98). Although
this may be an important finding, creatine kinase is not a direct
measure of protein breakdown. Also, the extent to which HMB or
KIC alone affected this attenuation of creatine kinase cannot be
determined. Another study that is commonly cited as evidence for
KIC supplementation and its ability to prevent proteolysis was
conducted on isolated rat diaphragm skeletal muscle (99). In this
venue, one should be cautious of overextrapolating from rodent
data to the human condition. At this point, there are not enough
data to conclude that KIC supplementation alone is an effective
anticatabolic supplement.
8.2. b-Hydroxy-b-Methylbutyrate
b-Hydroxy-b-methylbutyrate is a metabolite of the BCAA leu-
cine and is often associated with anticatabolic potential. The origi-
nal research study to highlight HMB’s anticatabolic potential was
conducted by Nissen and coworkers (100). In this study, untrained
subjects ingested one of three levels of HMB (0, 1.5, or 3.0 g/day)
and two protein levels (117 or 175 g/day) and resistance trained 3
days per week for 3 weeks. Other markers of muscle damage were
assessed, and protein breakdown was assessed by measuring urinary
3-methylhistidine (3-MH). After the first week of the resistance
training protocol, urinary 3-MH was increased by 94% in the
212 Campbell
control group and by 85% and 50% in individuals ingesting 1.5
and 3.0 g of HMB per day, respectively. During the second week
of the study, 3-MH levels were still elevated by 27% in the control
group but were 4% and 15% below basal levels for the groups on
HMB 1.5 and 3.0 g/day. Interestingly, 3-MH measures at the end
of the third week of resistance training were not significantly
different among the groups (100). Other studies demonstrating
an anticatabolic effect or suppressing muscle damage have sup-
ported the finding of this study (98,101). A study conducted by
van Someren and coworkers (98) instructed their male subjects to
ingest 3 g of HMB in addition to 0.3g KIC daily for 14 days prior
to performing a single bout of eccentrically biased resistance
exercise. This supplemental intervention that included HMB
resulted in a significant reduction in the plasma markers of muscle
damage.
Although HMB supplementation may suppress protein break-
down and markers of muscle damage, the main question is if this
anticatabolic effect leads to gains in lean body mass. The scientific
literature on this topic is divided. In a second arm to the study
conducted by Nissen and colleagues (100), male subjects ingested
3 g of HMB or a placebo for 7 weeks in conjunction with resistance
training 6 days per week. In this study, the fat-free mass increased in
the HMB-supplemented group at various times throughout the
investigative period but not at the conclusion of the study. Other
studies have also reported evidence for HMB supplementation
(3 g/day) relative to increasing lean body mass (102,103). In addi-
tion, a meta-analysis conducted by Nissen and Sharp (104) stated
that only HMB and one other sports supplement (creatine) were
found to increase lean body mass significantly.
Not all studies agree with the findings that HMB increases lean
body mass, however (105–107). Each of the studies showing no
effect of HMB on lean body mass accretion also supplemented their
subjects with approximately the same amount of HMB as the studies
that demonstrated increases in lean body mass. Although not con-
clusive, it appears that HMB supplementation does suppress protein
breakdown, ultimately leading to increased lean body mass in some
individuals. Following carbohydrate supplementation (for the pur-
pose of secreting insulin), HMB is the next best anticatabolic sports
supplement.
Muscle Mass and Weight Gain Nutritional Supplements 213
8.3. Glutamine
Another sports supplement commonly marketed as an anticata-
bolic agent is the amino acid glutamine. Glutamine is the most abun-
dant free amino acid in plasma and skeletal muscle and accounts for
more than half of the total intramuscular free amino acid pool (108).
The rationale for glutamine’s anticatabolic effects is the fact that it is
one of the major fuels used by the gut, resulting in a high cellular
turnover of glutamine in the gut (intestinal mucosal cells). This high
turnover may result in the supply of amino acids (glutamine) to the
cells of the gastrointestinal tract at the expense of skeletal muscle
protein. By providing supplemental glutamine to the gut, it theoreti-
cally spares the glutamine that is available in skeletal muscle and in this
way serves as an anticatabolic agent. One clinical investigation that
gave supplemental glutamine to individuals engaging in resistance
exercise did not demonstrate an anticatabolic potential or result in
increases in lean body mass (109). Other studies that have demon-
strated anticatabolic potential for glutamine have used critically ill
subjects or subjects who underwent surgery (110,111). Despite a valid
theoretical rationale for glutamine supplementation, at this point there
are no scientific data demonstrating that glutamine supplementation
suppresses protein breakdown in resistance trained individuals.
9. NITRIC OXIDE BOOSTERS
One of the more recent developments in sports supplements has
been the introduction of supplements intended to increase nitric oxide
production. Relative to biological processes in humans, nitric oxide is
synthesized in cells by nitric oxide synthase. One of nitric oxide’s
primary physiological functions is to relax smooth muscle, and
hence it is one of the body’s major regulators of blood flow, especially
during exercise. Kingwell (112) indicated that nitric oxide potentially
affects metabolic control during exercise via multiple mechanisms,
including:
Elevation in skeletal muscle and cardiac blood flow and increased deliv-
ery of oxygen, substrates, and regulatory hormones (e.g., insulin)
Preservation of intracellular skeletal muscle energy stores by promoting
glucose uptake, inhibiting glycolysis, mitochondrial respiration, and
phosphocreatine breakdown
214 Campbell
Together, these actions of nitric oxide on blood flow and sub-
strate utilization appear to be directed toward protection from
ischemia (112). Also, if adequate amounts of oxygen and substrate
are supplied to the skeletal muscle undergoing mechanical stress, the
possibility of extending the total workload on each set of a resistance
training bout may lead to greater stimulus for muscle fiber hyper-
trophy. The aforementioned observation, in conjunction with some
earlier studies showing nitric oxide as an integral compound relative
to improving skeletal muscle’s force production and maximal power
output (113,114), has provided a rationale for investigating ways to
increase endogenous nitric oxide production.
In every sports supplement claiming to augment endogenous
nitric oxide production, the amino acid arginine is included in the
list of ingredients. This is due to the fact that arginine serves as a
precursor for the biosynthesis of nitric oxide (115). In fact, arginine
is the only endogenous nitrogen-containing substrate of nitric oxide
synthase and thus governs production of nitric oxide. To date, only
one study has investigated the effects of an arginine-containing
sports supplement aiming at augmenting endogenous nitric oxide
production (116). Although this study was well designed, it should
be noted that nitric oxide production was not assessed in the clinical
investigation. The study investigated the effects of ingesting 12 g of
arginine a-ketoglutarate in conjunction with a periodized resistance
training program over a period of 8 weeks. Although there was some
improvement in some exercise performance variables, the investiga-
tors did not observe any increases in lean body mass. Specifically,
those ingesting arginine a-ketoglutarate had a significant increase
in upper body strength (as measured by the bench press) compared
to the subjects ingesting a placebo. In fact, those ingesting the
arginine a-ketoglutarate increased their bench press by 19 lb versus
an increase of approximately 6 lb in the placebo group. Addition-
ally, the arginine a-ketoglutarate group significantly increased their
peak power output (as measured by a 30-second cycle sprint test) in
comparison to the placebo group. Whether these improvements in
exercise performance can be associated with increases in nitric oxide
production is not known, but the fact remains that there were no
increases relative to lean body mass observed in this investigation.
At this point, there is a theoretical rationale that augmenting nitric
oxide production may lead to more intense training and ultimately
Muscle Mass and Weight Gain Nutritional Supplements 215
greater skeletal muscle hypertrophy. However, because clinical
investigations have not demonstrated this, it is premature to state
emphatically that sports supplements designed to increase nitric
oxide lead to greater gains in lean body mass.
10. CONCLUSION
Increasing lean body mass is a goal of many athletes, recreational
weight trainers, and those who wish to improve their body composi-
tion. When choosing a dietary supplement to augment increases in
lean body mass, it is important to consider the way in which the
supplement contributes to the highly regulated process of skeletal
muscle hypertrophy. The science of sports supplements is relatively
new, although certain sports supplements (protein, creatine) have
been scientifically investigated and have repeatedly demonstrated
their ability to increase lean body mass. Other sports supplements
(e.g., anticatabolic agents, anabolic hormone enhancers, nitric oxide
boosters) require more rigorous scientific investigation before they
can be deemed effective (or not).
REFERENCES
1. Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR. Increased rates of
muscle protein turnover and amino acid transport after resistance exercise in
humans. Am J Physiol 1995;268(Pt 1):E514–E20.
2. Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR. Mixed muscle
protein synthesis and breakdown after resistance exercise in humans. Am J
Physiol 1997;273(Pt 1):E99–E107.
3. Phillips SM, Tipton KD, Ferrando AA, Wolfe RR. Resistance training reduces
the acute exercise-induced increase in muscle protein turnover. Am J Physiol
1999;276(Pt 1):E118–E124.
4. Wagenmakers AJ. Tracers to investigate protein and amino acid metabolism in
human subjects. Proc Nutr Soc 1999;58:987–1000.
5. Trumbo P, Schlicker S, Yates AA, Poos M. Dietary reference intakes for
energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino
acids. J Am Diet Assoc 2002;102:1621–1630.
6. American College of Sports Medicine, American Dietetic Association, and
Dietitians of Canada. Joint position statement: nutrition and athletic perfor-
mance. Med Sci Sports Exerc 2000;32:2130–2145.
7. Tarnopolsky M. Protein requirements for endurance athletes. Nutrition
2004;20:662–668.
216 Campbell
8. Forslund AH, El-Khoury AE, Olsson RM, Sjodin AM, Hambraeus L, Young
VR. Effect of protein intake and physical activity on 24-h pattern and rate of
macronutrient utilization. Am J Physiol 1999;276(Pt 1):E964–E976.
9. Meredith CN, Zackin MJ, Frontera WR, Evans WJ. Dietary protein require-
ments and body protein metabolism in endurance-trained men. J Appl Physiol
1989;66:2850–2856.
10. Phillips SM, Atkinson SA, Tarnopolsky MA, MacDougall JD. Gender differ-
ences in leucine kinetics and nitrogen balance in endurance athletes. J Appl
Physiol 1993;75:2134–2141.
11. Lamont LS, Patel DG, Kalhan SC. Leucine kinetics in endurance-trained
humans. J Appl Physiol 1990;69:1–6.
12. Friedman JE, Lemon PW. Effect of chronic endurance exercise on retention of
dietary protein. Int J Sports Med 1989;10:118–123.
13. Tarnopolsky MA, Atkinson SA, MacDougall JD, Chesley A, Phillips S,
Schwarcz HP. Evaluation of protein requirements for trained strength athletes.
J Appl Physiol 1992;73:1986–1995.
14. Lemon PW, Tarnopolsky MA, MacDougall JD, Atkinson SA. Protein require-
ments and muscle mass/strength changes during intensive training in novice
bodybuilders. J Appl Physiol 1992;73:767–775.
15. Lemon PW. Protein and amino acid needs of the strength athlete. Int J Sport
Nutr 1991;1:127–145.
16. Antonio J, Stout J (eds). Sports Supplements. Lippincott Williams & Wilkins,
Philadelphia, 2001.
17. Boirie Y, Dangin M, Gachon P, Vasson MP, Maubois JL, Beaufrere B. Slow
and fast dietary proteins differently modulate postprandial protein accretion.
Proc Natl Acad Sci U S A 1997;94:14930–14935.
18. Fruhbeck G. Protein metabolism: slow and fast dietary proteins. Nature
1998;391:843, 845.
19. Dangin M, Boirie Y, Garcia-Rodenas C, et al. The digestion rate of protein is
an independent regulating factor of postprandial protein retention. Am J
Physiol Endocrinol Metab 2001;280:E340–E348.
20. Driskell J, Wolinsky I (eds) Energy-Yielding Macronutrients and Energy
Metabolism in Sports Nutrition. CRC Press, Boca Raton, FL, 2000.
21. Demling RH, DeSanti L. Effect of a hypocaloric diet, increased protein intake
and resistance training on lean mass gains and fat mass loss in overweight
police officers. Ann Nutr Metab 2000;44:21–29.
22. Kerksick CM, Rasmussen CJ, Lancaster SL, et al. The effects of protein and
amino acid supplementation on performance and training adaptations during
ten weeks of resistance training. J Strength Cond Res 2006;20:643–653.
23. Nikawa T, Ikemoto M, Sakai T, et al. Effects of a soy protein diet on exercise-
induced muscle protein catabolism in rats. Nutrition 2002;18:490–495.
24. Wolfe RR. Effects of amino acid intake on anabolic processes. Can J Appl
Physiol 2001;26(Suppl):S220–S227.
25. Bolster DR, Jefferson LS, Kimball SR. Regulation of protein synthesis
associated with skeletal muscle hypertrophy by insulin-, amino acid- and
exercise-induced signalling. Proc Nutr Soc 2004;63:351–356.
Muscle Mass and Weight Gain Nutritional Supplements 217
26. Kimball SR, Jurasinski CV, Lawrence JC Jr, Jefferson LS. Insulin stimulates
protein synthesis in skeletal muscle by enhancing the association of eIF-4E and
eIF-4 G. Am J Physiol 1997;272(Pt 1):C754–C759.
27. Biolo G, Declan Fleming RY, Wolfe RR. Physiologic hyperinsulinemia stimu-
lates protein synthesis and enhances transport of selected amino acids in human
skeletal muscle. J Clin Invest 1995;95:811–819.
28. Hillier TA, Fryburg DA, Jahn LA, Barrett EJ. Extreme hyperinsulinemia
unmasks insulin’s effect to stimulate protein synthesis in the human forearm.
Am J Physiol 1998;274(Pt 1):E1067–E1074.
29. Gore DC, Wolf SE, Sanford AP, Herndon DN, Wolfe RR. Extremity hyper-
insulinemia stimulates muscle protein synthesis in severely injured patients.
Am J Physiol Endocrinol Metab 2004;286:E529–E534.
30. Biolo G, Williams BD, Fleming RY, Wolfe RR. Insulin action on muscle
protein kinetics and amino acid transport during recovery after resistance
exercise. Diabetes 1999;48:949–957.
31. Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal
muscle protein synthesis and breakdown in man. J Clin Invest 1987;80:1–6.
32. Heslin MJ, Newman E, Wolf RF, Pisters PW, Brennan MF. Effect of hyper-
insulinemia on whole body and skeletal muscle leucine carbon kinetics in
humans. Am J Physiol 1992;262(Pt 1):E911–E918.
33. Denne SC, Liechty EA, Liu YM, Brechtel G, Baron AD. Proteolysis in skeletal
muscle and whole body in response to euglycemic hyperinsulinemia in normal
adults. Am J Physiol 1991;261(Pt 1):E809–E814.
34. Biolo G, Wolfe RR. Insulin action on protein metabolism. Baillieres Clin
Endocrinol Metab 1993;7:989–1005.
35. Bell JA, Fujita S, Volpi E, Cadenas JG, Rasmussen BB. Short-term insulin
and nutritional energy provision do not stimulate muscle protein synthesis if
blood amino acid availability decreases. Am J Physiol Endocrinol Metab
2005;289:E999–E1006.
36. Fujita S, Rasmussen BB, Cadenas JG, Grady JJ, Volpi E. Effect of insulin on
human skeletal muscle protein synthesis is modulated by insulin-induced
changes in muscle blood flow and amino acid availability. Am J Physiol
Endocrinol Metab 2006;291:E745–E754.
37. Tipton KD, Ferrando AA, Phillips SM, Doyle D Jr, Wolfe RR. Postexercise
net protein synthesis in human muscle from orally administered amino acids.
Am J Physiol 1999;276(Pt 1):E628–E634.
38. Paddon-Jones D, Sheffield-Moore M, Zhang XJ, et al. Amino acid ingestion
improves muscle protein synthesis in the young and elderly. Am J Physiol
Endocrinol Metab 2004;286:E321–E328.
39. Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR. Essential
amino acids are primarily responsible for the amino acid stimulation of muscle
protein anabolism in healthy elderly adults. Am J Clin Nutr 2003;78:250–258.
40. Levenhagen DK, Gresham JD, Carlson MG, Maron DJ, Borel MJ, Flakoll PJ.
Postexercise nutrient intake timing in humans is critical to recovery of
leg glucose and protein homeostasis. Am J Physiol Endocrinol Metab
2001;280:E982–E993.
218 Campbell
41. Rasmussen BB, Tipton KD, Miller SL, Wolf SE, Wolfe RR. An oral essential
amino acid-carbohydrate supplement enhances muscle protein anabolism after
resistance exercise. J Appl Physiol 2000;88:386–392.
42. Bird SP, Tarpenning KM, Marino FE. Liquid carbohydrate/essential amino acid
ingestion during a short-term bout of resistance exercise suppresses myofibrillar
protein degradation. Metabolism 2006;55:570–577.
43. Tipton KD, RasmussenBB, Miller SL, et al. Timing of amino acid-carbohydrate
ingestion alters anabolic response of muscle to resistance exercise. Am J Physiol
Endocrinol Metab 2001;281:E197–E206.
44. Tipton KD, Elliott TA, Cree MG, Wolf SE, Sanford AP, Wolfe RR. Ingestion
of casein and whey proteins result in muscle anabolism after resistance exercise.
Med Sci Sports Exerc 2004;36:2073–2081.
45. Tipton KD, Elliott TA, Cree MG, Aarsland AA, Sanford AP, Wolfe RR.
Stimulation of net muscle protein synthesis by whey protein ingestion before
and after exercise. Am J Physiol Endocrinol Metab 2007;292:E71–E76.
46. Borsheim E, Aarsland A, Wolfe RR. Effect of an amino acid, protein, and
carbohydrate mixture on net muscle protein balance after resistance exercise.
Int J Sport Nutr Exerc Metab 2004;14:255–271.
47. Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L,
Hespel P. Long-term creatine intake is beneficial to muscle performance during
resistance training. J Appl Physiol 1997;83:2055–2063.
48. Kelly V, Jenkins D. Effect of oral creatine supplementation on near-maximal
strength and repeated sets of high intensity bench press exercise. J Strength
Cond Res 1998;12:109–115.
49.VanLoonLJ,OosterlaarAM,HartgensF,HesselinkMK,SnowRJ,
Wagenmakers AJ. Effects of creatine loading and prolonged creatine
supplementation on body composition, fuel selection, sprint and endurance
performance in humans. Clin Sci (Lond) 2003;104:153–162.
50. Kreider RB, Ferreira M, Wilson M, et al. Effects of creatine supplementation
on body composition, strength, and sprint performance. Med Sci Sports Exerc
1998;30:73–82.
51. Branch JD. Effect of creatine supplementation on body composition
and performance: a meta-analysis. Int J Sport Nutr Exerc Metab
2003;13:198–226.
52. Gotshalk LA, Volek JS, Staron RS, Denegar CR, Hagerman FC, Kraemer WJ.
Creatine supplementation improves muscular performance in older men. Med
Sci Sports Exerc 2002;34:537–543.
53. Brose A, Parise G, Tarnopolsky MA. Creatine supplementation enhances
isometric strength and body composition improvements following strength
exercise training in older adults. J Gerontol A Biol Sci Med Sci 2003;
58:11–19.
54. Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG. Creatine
supplementation combined with resistance training in older men. Med Sci
Sports Exerc 2001;33:2111–2117.
55. Chromiak JA, Antonio J. Use of amino acids as growth hormone-releasing
agents by athletes. Nutrition 2002;18:657–661.
Muscle Mass and Weight Gain Nutritional Supplements 219
56. Burke DG, Smith-Palmer T, Holt LE, Head B, Chilibeck PD. The effect of
7 days of creatine supplementation on 24-hour urinary creatine excretion.
J Strength Cond Res 2001;15:59–62.
57. Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle
creatine loading in men. J Appl Physiol 1996;81:232–237.
58. Stout J, Eckerson J, Noonan D. Effects of 8 weeks of creatine supplementation
on exercise performance and fat-free weight in football players during training.
Nutr Res 1999;19:217–225.
59. Earnest CP, Snell PG, Rodriguez R, Almada AL, Mitchell TL. The effect of
creatine monohydrate ingestion on anaerobic power indices, muscular strength
and body composition. Acta Physiol Scand 1995;153:207–209.
60. Kreider RB, Klesges R, Harmon K, et al. Effects of ingesting supplements
designed to promote lean tissue accretion on body composition during
resistance training. Int J Sport Nutr 1996;6:234–246.
61. Volek JS, Duncan ND, Mazzetti SA, et al. Performance and muscle fiber
adaptations to creatine supplementation and heavy resistance training. Med
Sci Sports Exerc 1999;31:1147–1156.
62. Willoughby DS, Rosene J. Effects of oral creatine and resistance training on
myosin heavy chain expression. Med Sci Sports Exerc 2001;33:1674–1681.
63. Willoughby DS, Rosene JM. Effects of oral creatine and resistance training on
myogenic regulatory factor expression. Med Sci Sports Exerc 2003;35:923–929.
64. Lowe DA, Lund T, Alway SE. Hypertrophy-stimulated myogenic regulatory
factor mRNA increases are attenuated in fast muscle of aged quails. Am J
Physiol 1998;275(Pt 1):C155–C162.
65. Schultz E, McCormick KM. Skeletal muscle satellite cells. Rev Physiol
Biochem Pharmacol 1994;123:213–257.
66. Hawke TJ. Muscle stem cells and exercise training. Exerc Sport Sci Rev
2005;33:63–68.
67. Olsen S, Aagaard P, Kadi F, et al. Creatine supplementation augments the
increase in satellite cell and myonuclei number in human skeletal muscle
induced by strength training. J Physiol 2006;573(Pt 2):525–534.
68. Hameed M, Orrell RW, Cobbold M, Goldspink G, Harridge SD. Expression
of IGF-I splice variants in young and old human skeletal muscle after high
resistance exercise. J Physiol 2003;547(Pt 1):247–254.
69. Spangenburg EE. IGF-I isoforms and ageing skeletal muscle: an ‘unresponsive’
hypertrophy agent? J Physiol 2003;547(Pt 1):2.
70. Mero A, Miikkulainen H, Riski J, Pakkanen R, Aalto J, Takala T. Effects of
bovine colostrum supplementation on serum IGF-I, IgG, hormone, and saliva
IgA during training. J Appl Physiol 1997;83:1144–1151.
71. Mero A, Kahkonen J, Nykanen T, et al. IGF-I, IgA, and IgG responses to bovine
colostrum supplementation during training. J Appl Physiol 2002;93:732–739.
72. Mero A, Nykanen T, Keinanen O, et al. Protein metabolism and strength per-
formance after bovine colostrum supplementation. Amino Acids 2005;28:327–335.
73. Fernholm R, Bramnert M, Hagg E, et al. Growth hormone replacement
therapy improves body composition and increases bone metabolism in elderly
patients with pituitary disease. J Clin Endocrinol Metab 2000;85:4104–4112.
220 Campbell
74. Thoren M, Hilding A, Baxter RC, Degerblad M, Wivall-Helleryd IL, Hall K.
Serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and
the acid-labile subunit as serum markers of body composition during growth
hormone (GH) therapy in adults with GH deficiency. J Clin Endocrinol Metab
1997;82:223–228.
75. Ahmad AM, Hopkins MT, Thomas J, Ibrahim H, Fraser WD, Vora JP. Body
composition and quality of life in adults with growth hormone deficiency; effects of
low-dose growth hormone replacement. Clin Endocrinol (Oxf) 2001;54:709–717.
76. Alba-Roth J, Muller OA, Schopohl J, von Werder K. Arginine stimulates
growth hormone secretion by suppressing endogenous somatostatin secretion.
J Clin Endocrinol Metab 1988;67:1186–1189.
77. Merimee TJ, Rabinowitz D, Riggs L, Burgess JA, Rimoin DL, McKusick VA.
Plasma growth hormone after arginine infusion: clinical experiences. N Engl J
Med 1967;276:434–439.
78. Collier SR, Casey DP, Kanaley JA. Growth hormone responses to varying
doses of oral arginine. Growth Horm IGF Res 2005;15:136–139.
79. Isidori A, Lo Monaco A, Cappa M. A study of growth hormone release in man
after oral administration of amino acids. Curr Med Res Opin 1981;7:475–481.
80. Suminski RR, Robertson RJ, Goss FL, et al. Acute effect of amino acid
ingestion and resistance exercise on plasma growth hormone concentration in
young men. Int J Sport Nutr 1997;7:48–60.
81. Besset A, Bonardet A, Rondouin G, Descomps B, Passouant P. Increase in
sleep related GH and Prl secretion after chronic arginine aspartate administra-
tion in man. Acta Endocrinol (Copenh) 1982;99:18–23.
82. Colombani PC, Bitzi R, Frey-Rindova P, et al. Chronic arginine aspartate
supplementation in runners reduces total plasma amino acid level at rest and
during a marathon run. Eur J Nutr 1999;38:263–270.
83. Walberg-Rankin J, Hawkins C, Fild D, Sebolt D. The effect of oral arginine during
energy restriction in male weight trainers. J Strength Cond Res 1994;8:170–177.
84. Corpas E, Blackman MR, Roberson R, Scholfield D, Harman SM. Oral
arginine-lysine does not increase growth hormone or insulin-like growth
factor-I in old men. J Gerontol 1993;48:M128–M133.
85. Marcell TJ, Taaffe DR, Hawkins SA, et al. Oral arginine does not stimulate
basal or augment exercise-induced GH secretion in either young or old adults.
J Gerontol A Biol Sci Med Sci 1999;54:M395–M399.
86. Lukaski HC. Micronutrients (magnesium, zinc, and copper): are mineral
supplements needed for athletes? Int J Sport Nutr 1995;5(Suppl):S74–S83.
87. Lukaski HC. Magnesium, zinc, and chromium nutriture and physical activity.
Am J Clin Nutr 2000;72(Suppl):585S–593S.
88. Kikukawa A, Kobayashi A. Changes in urinary zinc and copper with strenuous
physical exercise. Aviat Space Environ Med 2002;73:991–995.
89. Nielsen FH, Lukaski HC. Update on the relationship between magnesium and
exercise. Magnes Res 2006;19:180–189.
90. Buchman AL, Keen C, Commisso J, et al. The effect of a marathon run on
plasma and urine mineral and metal concentrations. J Am Coll Nutr
1998;17:124–127.
Muscle Mass and Weight Gain Nutritional Supplements 221
91. Brilla L, Conte V. Effects of a novel zinc-magnesium formulation on
hormones and strength. J Exerc Physiol Online 2000;3:26–36.
92. Wilborn C, Kerksick CM, Campbell B, et al. Effects of zinc magnesium
aspartate (ZMA) supplementation on training adaptations and markers of
anabolism and catabolism. J Int Soc Sports Nutr 2004;1:12–20.
93. Om AS, Chung KW. Dietary zinc deficiency alters 5 alpha-reduction and
aromatization of testosterone and androgen and estrogen receptors in rat
liver. J Nutr 1996;126:842–848.
94. Neychev VK, Mitev VI. The aphrodisiac herb Tribulus terrestris does not
influence the androgen production in young men. J Ethnopharmacol
2005;101:319–323.
95. Willoughby DS, Wilborn C, Taylor L, Campbell B. Eight weeks of aromatase
inhibition using the nutritional supplement Novedex XT: effects in young,
eugonadal men. Int J Sport Nutr Exerc Metab 2007;17:92–108.
96. Fryburg DA, Barrett EJ, Louard RJ, Gelfand RA. Effect of starvation on
human muscle protein metabolism and its response to insulin. Am J Physiol
1990;259(Pt 1):E477–E482.
97. Fryburg DA, Louard RJ, Gerow KE, Gelfand RA, Barrett EJ. Growth
hormone stimulates skeletal muscle protein synthesis and antagonizes
insulin’s antiproteolytic action in humans. Diabetes 1992;41:424–429.
98. Van Someren KA, Edwards AJ, Howatson G. Supplementation with beta-
hydroxy-beta-methylbutyrate (HMB) and alpha-ketoisocaproic acid (KIC)
reduces signs and symptoms of exercise-induced muscle damage in man. Int J
Sport Nutr Exerc Metab 2005;15:413–424.
99. Tischler M, Goldberg A. Does leucine, leucyl-tRNA, or some metabolite of
leucine regulate protein synthesis and degradation in skeletal and cardiac
muscle? J Biol Chem 1982;257:1613–1621.
100. Nissen S, SharpR, Ray M, et al. Effect of leucine metabolite beta-hydroxy-beta-
methylbutyrate on muscle metabolism during resistance-exercise training.
J Appl Physiol 1996;81:2095–2104.
101. Knitter AE, Panton L, Rathmacher JA, Petersen A, Sharp R. Effects of
beta-hydroxy-beta-methylbutyrate on muscle damage after a prolonged run.
J Appl Physiol 2000;89:1340–1344.
102. Jowko E, Ostaszewski P, Jank M, et al. Creatine and beta-hydroxy-beta-
methylbutyrate (HMB) additively increase lean body mass and muscle
strength during a weight-training program. Nutrition 2001;17:558–566.
103. Gallagher PM, Carrithers JA, Godard MP, Schulze KE, Trappe SW. Beta-
hydroxy-beta-methylbutyrate ingestion. I. Effects on strength and fat free
mass. Med Sci Sports Exerc 2000;32:2109–2115.
104. Nissen SL, Sharp RL. Effect of dietary supplements on lean mass and
strength gains with resistance exercise: a meta-analysis. J Appl Physiol
2003;94:651–659.
105. Kreider RB, Ferreira M, Wilson M, Almada AL. Effects of calcium beta-
hydroxy-beta-methylbutyrate (HMB) supplementation during resistance-training
on markers of catabolism, body composition and strength. Int J Sports Med
1999;20:503–509.
222 Campbell
106. Slater G, Jenkins D, Logan P, et al. Beta-hydroxy-beta-methylbutyrate
(HMB) supplementation does not affect changes in strength or body compo-
sition during resistance training in trained men. Int J Sport Nutr Exerc Metab
2001;11:384–396.
107. Vukovich MD, Stubbs NB, Bohlken RM. Body composition in 70-year-old
adults responds to dietary beta-hydroxy-beta-methylbutyrate similarly to that
of young adults. J Nutr 2001;131:2049–2052.
108. Curthoys NP, Watford M. Regulation of glutaminase activity and glutamine
metabolism. Annu Rev Nutr 1995;15:133–159.
109. Candow DG, Chilibeck PD, Burke DG, Davison KS, Smith-Palmer T. Effect
of glutamine supplementation combined with resistance training in young
adults. Eur J Appl Physiol 2001;86:142–149.
110. Hammarqvist F, Wernerman J, Ali R, von der Decken A, Vinnars E.
Addition of glutamine to total parenteral nutrition after elective abdominal
surgery spares free glutamine in muscle, counteracts the fall in muscle protein
synthesis, and improves nitrogen balance. Ann Surg 1989;209:455–461.
111. Vinnars E, Hammarqvist F, von der Decken A, Wernerman J. Role of
glutamine and its analogs in posttraumatic muscle protein and amino acid
metabolism. JPEN J Parenter Enteral Nutr 1990;14(Suppl):125S–129S.
112. Kingwell BA. Nitric oxide-mediated metabolic regulation during exercise:
effects of training in health and cardiovascular disease. FASEB J
2000;14:1685–1696.
113. Morrison RJ, Miller CC 3rd, Reid MB. Nitric oxide effects on shortening
velocity and power production in the rat diaphragm. J Appl Physiol
1996;80:1065–1069.
114. Morrison RJ, Miller CC 3rd, Reid MB. Nitric oxide effects on force-velocity
characteristics of the rat diaphragm. Comp Biochem Physiol A Mol Integr
Physiol 1998;119:203–209.
115. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med
1993;329:2002–2012.
116. Campbell B, Roberts M, Kerksick C, et al. Pharmacokinetics, safety, and
effects on exercise performance of L-arginine alpha-ketoglutarate in trained
adult men. Nutrition 2006;22:872–881.
Muscle Mass and Weight Gain Nutritional Supplements 223
