Connective Tissue Part II: The Good, The Bad and the Ugly
Source: Mesomorphosis
Author: Elzi Volk
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In Part I of
this series, readers were introduced to basic histology and physiology
of connective tissue. We learned that all connective tissue has similar
components, although the proportions of these components vary. These
variations impart the mechanical and biochemical attributes to specific
connective tissue. To illustrate, mechanical properties of articular
cartilage that allow it to absorb impact and resist wear are partially
due to the large proteoglycan aggregates.
We also learned that each component of connective
tissue is built up with modular pieces. Each of these molecular modules
requires energy and catalysts, such as enzymes and cofactors, for every
given reaction of synthesis. Therefore any alteration in the synthesis
or degradation of a module will affect its ultimate constitution. When
there are numerous altered modules, a domino effect may eventually
modify the complex community of macromolecules and result in changed
characteristics of a tissue.
Many modulators influence turnover of connective
tissue components and tissue remodeling. Recall from Part 1 that these
modulators may be growth factors, hormones, cytokines, enzymes, and
basic building blocks such as amino acids and carbohydrates. When
dietary constituents or pharmaceuticals alter normal function of these
modulators, resulting modified mechanical and metabolic characteristics
may impair the normal biomechanics of a given connective tissue.
Before examining the influences of nutrition and
pharmaceuticals on connective tissue, three types of dense connective
tissue that are most important to athletes will be briefly described.
These three types are tendons, ligaments and articular cartilage.
Details of biomechanics will not be examined except where
physiologically relevant. Readers who are interested in learning more
about biomechanics are referred to textbooks on the subject.
Tendons
Skeletal muscle and tendons are distinct tissues.
However, they function as one unit: the musculo-tendon unit. Tendons
attach the muscle to bones and transmit force from the muscle to the
bone. Connective tissue forms a network throughout the muscle. It
surrounds the fibers, the bundles of fibers and wraps around the whole
muscle. This connective tissue network is continuous through the muscle
and into the tendon that inserts the bone. Although the entire framework
is essential to the function of the musculo-tendon unit, the tendon will
be the focus of this discussion.
Tendons primarily consist of collagen – up to 85% of
the dry weight – which imparts the mechanical and physiological
properties of this tissue. Type I collagen predominates with small
amounts (approximately 5%) of Type III and Type V collagen. Smaller
amounts of elastin exist in the extracellular matrix. The type and
quality of cross-linking varies in tendon fibers and is associated with
the degree of mechanical loading experienced by the musculo-tendon unit.
The regulation of the cross-link quality in new collagen is established
by the mechanical loading during growth and development. Tendons that
transmit the highest forces have the highest degree of cross-linking.
Mechanical forces also determine morphology of collagen. The distal end
of human tibialis posterior tendon, which receives compressive forces as
well as tensional forces, exhibited less linear and more swirled
collagen formation than seen in the proximal end (which receives mostly
tensional forces).
Proteoglycans (PGs) in the tendon extracellular matrix
are typically of two major classes that differ in structure and
function. In general, the large cartilage-type proteoglycan monomers are
present in low concentrations and the smaller dermatan sulfate
proteoglycans (DS-PGs) are present in high concentrations. However, in
tendons that are subject to compressive loads, the concentration of
cartilage-type PGs is increased to impart special biomechanical
properties to the tissues. The DS-PGs regulate the growth and size of
the collagen fibrils during tendon development and repair.
Vogel et al (1) demonstrated morphological and PG
heterogeniety in tendon and ligaments excised from human cadavers of
various ages. Different cell shapes and concentration and type of
glycosaminoglycans (GAGs) exist between the distal and proximal ends of
tendons. Similar differences exist along the length and in the thickness
of the tissues. The PG content of the tendon region that experiences
compression and tensional forces (e.g. in the region of the tendon that
passes under or around a bone) increases by as much as three times that
of the tensional region. Increased concentration of large PG content may
enhance a tissue’s compressive stiffness.
The closely packed fibers are bundled together and run
parallel to the long axis of the tendon. Fibroblasts are few and located
in the spaces between the collagen bundles. Many collagen bundles
grouped together form the fascicle, and a synovial-like membrane, the
epitenon, surrounds several fascicles to form the tendon unit. This
membrane contains blood and lymphatic vessels and nerves. Several layers
of elastic connective tissue sheaths enclose the tendon unit. The
properties of these layers vary depending on site. Some tendons (such as
the flexor tendons in forearm) are enclosed by a synovial sheath which
carries many blood vessels.
The nerve supply to tendons and ligaments originates
from the nerves of the muscles. Tendons are well vascularized: less than
muscle and more than ligaments. Degree of vascularity differs depending
on structure and site of the tissue. Blood vessels within the tendonous
tissue are relatively sparse. Altered blood flow and consequent
production or accumulation of soluble factors may modulate the type and
amounts of PGs and collagen. The more vascularized tendons have blood
vessels that infiltrate throughout the tendon from the outer connective
sheath. The less vascular tendons have outer membranes that act as
conduits of blood supply for the tendon fibers within. The other source
of nutrition is diffusion from the synovial fluid which provides a
significant supply of nutrients for many tendons. The tissues enclosing
and surrounding the tendon provide a cellular and vascular component for
healing and providing nutrition to the tissue within.
Ligaments
Ligaments are bands of connective tissue that bind
bones to each other, crossing joints with wide ranges of motion as well
as joints with little motion. Unlike tendons, both ends of ligaments
insert into bone. The tissue may exist as fibrous bands, sheets or short
thickened strips in joint capsules. Unlike previous assumptions,
ligaments and tendons differ from each other in several ways. Collagen
content is generally similar in tendons and ligaments. Type I collagen
predominates (90%) with small amounts of type III (10%), which is more
than tendons. Ligamentous collagen has more reducible cross-linking. The
tightly packed bundles of collagen with many fibroblasts are aligned
along the axis of tension.
As in tendons, site-specific structural and
biochemical differences exist in ligaments due to different mechanical
demands and the nutritional environment. The elastin content in
ligaments varies depending on function. Most ligaments have less than 5%
elastin. However, others have higher concentrations (up to 75%)
imparting more elastic properties. Intraligamentous blood vessels are
sparse. Therefore, mid-tissue nutrition relies greatly on diffusion from
nearby blood vessels which lie parallel to the tissue and synovial
fluid.
Many ligaments contain more GAGs than tendons. As
well, ligaments contain the three major types of PGs (1): the small PGs,
decorin and biglycan, and the larger PGs. The smaller PG, decorin, is
the major type of PG in tendons. How these differences affect the
tensile strength is not elucidated.
The nerve supply to ligaments is similar to that of
tendons: primarily supplied from the nerves of the muscles acting on the
joint. However, numerous free nerve endings in ligaments may moderate
pain sensation.
More than tendons, most information on ligament
injuries and repair are based on animal models where ligaments are
partially or completely cut. Studies demonstrate the substantial
differences in the site-specific repair process in ligaments as well as
tendons. Animal models show varying healing capacities for various
ligaments. Because ligaments are generally less vascularized than
tendons, the healing and repair process takes much longer and, in some
ligaments, may regress or disappear completely. Studies demonstrate that
remodeled tissue never achieves normal characteristics nor a return to
original mechanical properties. Mature repaired ligament tissue lacks
the strength of normal ligaments: usually 50-70% of normal tensile
strength (2).
The Vogel et al (1) study validated the use of animal
tissue models to study the cellular mechanisms that cause site-specific
changes in connective tissue morphology. While this may be true for
normal adaptive responses, differences in metabolism may limit
extrapolations to nutrition and pharmaceuticals. Human and animal
studies confirm that the amount of PGs that accumulate in specific
regions of tendons is directly correlated with compressive and tensional
loads placed on the tissue.
Articular Cartilage
A joint is a junction of two bones, holding them
together while allowing for smooth movement against one another. The
joint capsule and fibrous lining holds many components where the
bone-ends meet. The synovial cavity, which is surrounded by a membrane,
contains fluid that lubricates and nourishes the articular cartilage,
the tissue that caps the ends of the bones.
In addition to supplying nutrients to cartilage,
synovial fluid contains phygocytic cells that remove debris resulting
from wear and tear in the joint capsule. The amount of fluid in the
synovium varies depending on the size of the joint. The fluid is
normally viscous when there is no joint movement; as movement increases,
the fluid becomes less viscous.
Cartilage is a resilient material that absorbs shock
and provides an elastic surface for smooth gliding of joints.
Chondrocytes are embedded in the extracellular matrix comprised of type
II collagen, proteoglycans and water. Cartilage lacks blood vessels,
nerves and a lymphatic system. The cells must therefore rely on
diffusion of nutrients through the extracellular matrix from the
underlying bone or the synovial fluid. Damage to articular cartilage may
be present long before it is noticed since these joints are
non-innervated. Peripheral activation and sensitization of nerves during
inflammation may elicit pain well after degenerative processes are
stimulated.
The extracellular matrix is of great importance to the
cartilage. Recall from Part I that collagen fibers and the ground
substance make up the extracellular matrix. Collagen fibers and the
glycoproteins comprise the fibrous web that anchors the chondrocytes
within the matrix and provide tensile strength to cartilage. The
fundamental component in the ground substance is the GAGs. The large
proteoglycan aggregates described in Part I play an important role in
maintaining optimal function of our joints.
In cartilage, the predominant GAGs are chondroitin
sulfate and keratan sulfate. As was discussed in Part I, the PG monomers
link to hyaluronic acid to form large aggregates. Recall that these
large PGs are highly negatively charged, repelling one another and
attracting water which makes up 80% of the wet weight of articular
cartilage. These PGs provide the compressive strength to the joints.
When the joint is loaded the matrix compresses and water is squeezed out
of the matrix. When the compressive force is removed, the negatively
charged GAGs reabsorb water. Also, the high content of GAGs in the
synovial fluid provides lubrication minimizing wear between the two
joints.
Considering the importance of the extracellular matrix
to normal physiology and function of articular joints, any factor that
increases the ratio of degradation to loss of matrix components will
cause cartilage health to deteriorate. Alterations in cellular activity
may also affect the turnover rate and remodeling process.
PATHOPHYSIOLOGY
Most connective tissue injuries involve damage to the
structural components of the tissue. In sports activities, injuries are
classified into two types: acute and overuse injuries. Acute
traumas occur from lacerations and partial or complete rupture of the
tissue. These injuries heal by the repair process described in Part I.
Overuse injuries, the most common category, result from chronic
overloading or repetitive motion. The capacity of the tissue for repair
greatly exceeds degradation and cellular metabolism is altered such that
damage occurs at the cellular and structural levels.
Inflammation is the most prominent symptom of both
types of injuries. As discussed in Part I, inflammation is a natural
part of the healing process in any injury. However, chronic inflammation
may lead to increased tissue degradation and impair the repair process.
Indeed, chronic inflammation is a major factor in several connective
tissue diseases, especially within articular joints. Pharmaceuticals are
often used to manage or alleviate symptoms occurring with connective
tissue inflammation. However, many of these exogenous substances may
alter the healing and repair process.
Metabolic states, such as aging and diabetes, may also
affect connective tissue health. Aging is often accompanied by a decline
in joint function or general stiffness of the joints, and influences the
nature and extent of the repair process in injured tissue. As connective
tissues age, the composition of collagen and proteoglycans change which
in turn alters the mechanical properties and physiology of the tissue.
The tissue cells lose their ability to divide, especially in articular
cartilage where the chondrocytes are poorly nourished. PGs produced from
aging chondrocytes are very different from those produced by younger
cells and alters the hydrostatic properties of the joint.
Species, site, zone and region of connective tissue
dictate changes, both qualitative and quantitative, in PGs. However, age
has the most notable effect on composition and stability of the
extracellular matrix. PGs in the matrix have a protective effect on the
collagen network. Continued loss of PGs and other matrix components
appear to activate loss of collagen from connective tissues. For
instance, a reduction of the size of hyaluronan and reduced stability of
the GAG chains are age related. Studies (1,4) validate that
concentration of small PG monomers increases with age. The resulting
decrease in load absorption and redistribution properties is less
efficient and renders the tissue more prone to damage.
Vogel et al showed that generally the alterations in
the pattern of morphology and proteoglycan composition varied little in
tendons with increasing age after puberty. However, PGs from tendons of
younger individuals had greater homogeneity in GAG chain length. Effects
of aging, however, may be tissue and site specific. For example, some
ligaments maintain their mechanical characteristics throughout the life
of the organism, whereas others show deterioration of strength with
advanced age. Amount and composition of proteoglycans in human
ligamentum flavum of the spine changed with age contributing to the
ossification (calcification) of the tissue (3).
Osteoarthritis (OA) is the most common degenerative
disease associated with aging of joint connective tissue. Degradation of
the extracellular matrix is responsible for the pathogenesis of OA and
is frequently associated with predisposing conditions such as traumatic
injury to the joint. Chondrocytes in articular cartilage with OA may be
unresponsive to local growth factors resulting in decreased synthesis of
matrix components. Increased amounts of catabolic substances reduce
concentrations of proteoglycans and glycoproteins resulting in
reductions in tensile strength and resiliency.
Changes in connective tissue in diabetics parallel
those evident in aging and cause many complications seen in later stage
diabetes. The most apparent clinical disorders affect the skin, eyes,
arteries and kidneys. Arteries and joints of diabetics become
prematurely stiff with decreased elasticity. Nonenzymatic glycation of
collagen protein and oxidative stress are associated with aging and
diabetes, and caused by hyperglycemia (‘glucose toxicity’) (4,5,6
,7, 8). Excessive plasma and tissue glucose undergo reactions that
produce advanced glycation products. The long-lived proteins of collagen
and elastin accumulate enough advanced glycation products that
irreversibly alter many of the protein’s physical properties. The
collagen becomes saturated and excessively cross-linked inhibiting
normal turnover. Progressive changes in properties ultimately modify
arrangements and functioning of the tissue (8). These alterations in the
matrix may affect cell behavior such as migration, growth, proliferation
and gene expression.
Glycation is the nonenzymatic reaction between a sugar
and the free amino acid group of proteins. Several mechanisms initiate
glycation including glucose auto-oxidation and the Amadori degradation
pathway. Lipid peroxidation (oxidation of polyunsaturated fatty acids)
may also contribute to oxidative reactants. Intermediates of
carbohydrate peroxidation are similar to lipid peroxidation; both form
carboxymethyllysine (CML). Under oxidative conditions and in the
presence of a transition metal, such as copper or iron, CML forms and
accumulates in tissue, altering collagen cross-linking. Other advanced
glycation products also affect the physical, chemical and mechanical
properties of collagen protein. Collagen becomes browned and excessively
cross-linked, altering its tensile strength. Diabetic rats exhibit
acceleration of procollagen degradation in tendons (9). An
interventional strategy that shows success in animal models is glycemic
control and is discussed further along with carbohydrate nutrition.
Excessive or high-intensity exercise may be traumatic
to the body’s skeletal system and result in acute or overuse injuries
that are discussed previously. Low-intensity exercise is not considered
to be injurious to a healthy normal individual. In fact, immobilization
can impair normal metabolism and remodeling of connective tissue. When a
joint is immobilized, the diminished mechanical loading and unloading of
cartilage and surrounding tissues interferes with normal turnover of
cells and matrix components. Decreased stimulation of cells results in
decreased proteoglycan synthesis. Consequently, matrix loss leads to
increased vulnerability of the tissue to injury when normal activities
are resumed.
Studies in animal models have shown exercise to be
beneficial to healthy metabolism of connective tissues. Brown et al (10)
measured urine levels of hydroxyproline (HP), hydroxylysine (HL) and
pyridinoline (PYD) as indirect markers of connective tissue breakdown
and remodeling after a bout of eccentric exercise. These amino acid
biomarkers characteristic to cross-linking are released during breakdown
and remodeling of collagen and elastin. Post-exercise levels of urine
HP, HL and PYD increased indicating that eccentric exercise may disrupt
skeletal muscle and connective tissue structures. The delay (two days
after exercise bout) in increased biomarker levels suggest that
breakdown is not immediate and does not result directly from mechanical
damage to connective tissue. Otherwise, urine biomarker levels should
increase within 24 hours. The authors suggest that connective tissue
breakdown results from the localized inflammatory response to
exercise-induced musculo-tendon trauma. Inflammatory mediators from
inflammation in the musculo-tendon unit may promote collagen breakdown
and subsequent synthesis in surrounding connective tissues.
Exercise may contribute to long- and short-term
stimulation of cartilage metabolism by mechanical loading of the joints.
Compression of the joint capsule induced by mechanical loading changes
joint fluid and pressure, osmotic pressure, cell-matrix interactions and
cell activities. In animal models (11), post-exercise PG synthesis was
enhanced and breakdown was reduced in the carpel joint synovial fluid.
Cartilage degradation was impaired and the extracellular matrix was more
stable. Several studies (10,11) suggest that the effects of mechanical
loading on articular cartilage metabolism is mediated by changes in
composition and humoral factors released into the synovial fluid.
NUTRITION AND CONNECTIVE TISSUE
As many athletes know, exercise may increase turnover
of muscle and connective tissue by elevated breakdown and synthesis.
Nutritional aspects of muscle tissue remodeling are routinely addressed
in weightlifting and fitness periodicals. However, connective tissue
receives little attention except for occasional mention in training
techniques and programs. Supplement companies have recently begun to add
nutritional supplements to their product lines for connective tissue.
Unfortunately, weight lifters (and the general public) generally know
less about physiology of connective tissue than muscle tissue and may be
confused with supplement advertisement claims. Some of these products
may indeed benefit connective tissue health and integrity. Nonetheless,
they can not replace a proper diet. Let us take a look at the
nutritional macronutrients and discuss how they influence connective
tissue turnover and remodeling.
Nearly all knowledge gathered about the nutritional
influences on human connective tissues is extrapolated from
investigations with in vitro tissue/cell research, animal models, and
clinical and surgical practice. Human in vivo investigations are costly
and relatively difficult because serum levels of nutrients ordinarily
inadequately reflect total body content. Measuring total body level of
specific nutrients is complex and sometimes impossible. As well,
measuring direct clinical effects on specific tissues resulting from
individual nutrients in humans is equally complicated. Nearly all human
measurements are indirect and from clinical studies.
Calories (12,13,14)
Many studies demonstrate that collagen production is
sensitive to changes in short and long-term food intake. Within 24 hours
of fasting of some animal models, collagen synthesis in articular
cartilage decreases to 50% of normal. This reduction declines to 8-12%
of control levels after 96 hours. Most conditions are not as severe as
starvation. However, energy restriction may reduce collagen synthesis
depending on duration and degree of food deprivation. Specific effects
of malnutrition on connective tissue turnover are dependant on many
factors such as exercise activities, injuries, and disease. As well,
nutrition restriction effects may be age-related. Youngsters that are
still growing are more sensitive to nutritional changes. Replacement of
tissue pools of macronutrients requires weeks to months and certainly
affects turnover rates of tissue components. Likewise, dietary
deficiencies or excess and physical activities influence turnover rates.
Calories provide the body with cellular energy for
normal metabolism, building and repairing tissues and stimulate hormonal
responses. Individuals with injuries or other trauma should avoid a
decrease in calories below maintenance or slightly above, thereby
providing the nutrients and energy needed for healing and repair.
Considering that connective tissue structures are created from all
macronutrients, each are discussed below.
Protein (12,13,14)
Severe caloric restriction is usually accompanied by
protein deficiency. The two major sources of protein during times of
bulk loss are muscle and connective tissue. Muscle tissue provides a
steady source amino acids (AAs) for general body needs. Connective
tissue is the second source, which is reflective of the relative rate of
turnover to muscle tissue. Many studies have demonstrated that a protein
deficient diet results in a reduction of growth and development of the
organism as well as delay in wound healing and repairs.
All of the essential AAs are required for synthesis of
proteins and other components and growth factors in the extracellular
matrix. Some studies show that supplementing certain individual AAs
(methionine, lysine, arginine, and proline) to a protein deficient diet
may inhibit prolongation of the inflammation phase of connective tissue
healing and aid in fiber cross-linking mechanisms during repair.
Although countless studies demonstrate that protein
malnutrition is significantly detrimental to normal turnover and healing
of connective tissues, most athletes are generally well nourished with
protein intake. Unless an individual is presented with severe trauma,
surgery, or diabetes, a protein deficit that would negatively affect
normal connective tissue metabolism should not be an issue.
For more general information on dietary protein and
metabolism, read the series of articles by Lyle McDonald in past issues
of Mesomorphosis.
Carbohydrates (12,14)
Aside from protein, carbohydrates are a major
component of an athlete’s diet and supply quick energy for the body in
the form of glucose. Although little information exits on the direct
effects of glucose deficiencies on connective tissues, it is well known
that glucose is an energy source for several components and growth
mediators. Phagocytes and other white cells that mediate the
inflammatory process utilize glucose as an energy source. Activity by
these cells during the acute and healing phases prepare tissue for
repair after injury. Tissue cells such as fibroblasts and chondroblasts
require glucose for synthesis of various macromolecules. Glucose is a
building block of glycosaminoglycans and glycoproteins in the ground
substance of the matrix. Arguably, hypoglycemia (abnormally low level of
plasma glucose) impairs normal cell function and delays wound healing.
As well, production and release of several hormones, such as insulin and
growth hormone, decline with low levels of plasma glucose further
delaying tissue growth and repair.
Conversely, high levels of plasma glucose may also be
detrimental. Decreased insulin function may lead to hyperglycemia
(abnormally high levels of plasma glucose) which also impairs wound
healing. High levels of plasma glucose reportedly may inhibit the
stimulatory action of ascorbic acid on proteoglycan and collagen
production (15). Furthermore, recall that chronic high plasma and tissue
glucose levels produce advanced glycation products that affect the
physical, chemical and mechanical properties of collagen and elastin
protein. Although associated with aging, this process is prematurely
evident in diabetics. Proper glycemic control may delay the onset of
complications related to excessive glycation and oxidation stress (6).
For diabetics, exogenous insulin may be necessary for glycemic control.
Additionally, avoiding a diet with excessive carbohydrate intake may
postpone effects of high accumulation of glycation and oxidative
products.
Diets low in carbohydrates typically cause body water
loss. For athletes, the resultant dehydration may compromise integrity
of connective tissues subject to mechanical loading. Considering that
many connective tissues such as in articular joints require a relatively
high water content for optimal functioning under stress, dehydration may
increase incidence of injury or jeopardize healing and repair of injured
tissue.
Fats (16,17)
Fats are very calorically dense and provide energy for
the body. Furthermore, saturated fats and polyunsaturated fatty acids
(PUFAs) are precursors for many hormones such as steroids and
prostaglandins. PUFAs are essential constituents of the cell membrane,
contributing to their structural and functional integrity. Saturated
fats are commonly found in animal foods and in some vegetable plants and
have little direct import in the physiology of connective tissue.
Therefore, discussion will concentrate on the influences of PUFAs and
their influence on injured connective tissue.
The major PUFAs are classified as two types: n-3 and
n-6 PUFAs. The n-6 family is the major PUFA in cell membranes and is
derived from vegetable oils. Low levels of n-3 PUFAs exist in most
individual cell membranes because diets are generally low in fish oils
which are the source of this PUFA family. PUFAs are precursors for a
family of hormones called eicosanoids, which are released by macrophages
and other cells and mediate many cellular functions. These substances
have powerful autocrine (act on cell where released) and paracrine (act
on nearby cell) actions. The major role of eicosanoids is in the
inflammatory response; therefore, dietary PUFAs may moderate the length
of the inflammatory phase.
The n-6 PUFAs are precursors for arachidonic acid and
the series 1 and 3 eicosanoids. Eicosapentanoic acid and eicosanoid
series 2 are formed from the n-3 PUFAs. Generally, the 1 and 3
eicosanoid series are anti-inflammatory and the series 2 eicosanoids are
pro-inflammatory. A relative excess of n-6 PUFAs stimulates production
of prostaglandin E2 which may prolong the inflammatory
response.
Dietary n-3 PUFAs can replace n-6 PUFAs. Increasing
the ratio of dietary n-3:n-6 PUFAs may decrease macrophage prostaglandin
E2 and cytokine release, and a balance between the
eicosanoids may maintain the repair process with the least amount of
inflammation. Although increasing intake of n-3 PUFAs may not impact
acute inflammation, such nutritional support quite possibly moderate
long-term inflammation related to excessive prostaglandin E2
production and cytokine release from activated macrophages.
As we have seen, dietary macronutrient deficiencies
and excesses influence metabolism of connective tissue components during
growth, stress, and repair. As well, vitamins and minerals play
significant roles in connective tissue metabolism and will be addressed
in Part 3 of this series. Conceivably, nutrition may be used as adjunct
therapy for tissue repair. However, most commonly, pharmaceuticals are
used to moderate symptoms of inflammation resulting from injuries and
may potentially interfere with normal turnover or repair of tissues.
Some of these applications, including nutriceuticals, will be examined
in Part 3 along with their effects on connective tissue physiology.
Please send us your feedback on
this article.
Elzi Volk
elzi@thinkmuscle.com
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