high - intensity eccentric exercise is known to induce muscle damage ( clarkson and hubal , 2002 ) .
morphologically , muscle damage leads to cell membrane disruption ( nosaka et al . , 2006 ) , infiltration of inflammatory cells , such as neutrophils and macrophages , into the site of damage ( clarkson and hubal , 2002 ; tidball , 2005 ) , and degradation of the extracellular matrix ( ecm ) ( kjaer et al . ,
fragments resulting from ecm degradation facilitate the mobilization of cells related to the inflammatory response and increase chemotactic activity and phagocytosis , ultimately playing a role in the development of delayed onset muscle soreness ( stauber et al . ,
1990 ) . increased ecm degradation following muscle damage has also been reported to reduce force transmission ( gao et al . , 2008 ) .
however , ecm degradation also facilitates the movement and regeneration of satellite cells ( chen and li , 2009 ) .
several enzymes play important roles in ecm degradation ; of these enzymes , matrix metalloproteinases ( mmps ) and tissue inhibitor of metalloproteinases ( timps ) have been extensively studied ( kieseier et al . , 2001 ) .
mmps have been reported to degrade ecm ( mu et al . , 2010 ; rullman et al . ,
2013 ) , whereas timps inhibit the enzymatic functions of mmps ( alameddine , 2012 ) .
excessive activation of mmps increases tissue degradation , hindering myogenesis ( kieseier et al . ,
hence , the balance between mmps and timps must be well managed to optimize postdamage ecm remodeling .
koskinen et al . ( 2002 ) reported that high - intensity eccentric muscle contraction significantly increases mmp-2 and mmp-9 expression .
2004 ) reported that mmp-9 and timp-1 levels are significantly increased following eccentric exercise . in contrast , nascimento et al .
( 2016 ) reported that mmp-2 and -9 levels actually decrease after eccentric exercise , whereas madden et al .
although recent studies of exercise - induced muscle damage have focused on mmp and timp responses following eccentric exercise , the importance of ecm degradation regulated by mmp and timp during recovery from muscle damage is not well recognized .
in fact , mmp and timp responses have been documented in the field of cancer and chronic inflammatory diseases .
therefore , this mini - review will discuss mmp and timp responses to muscle damage following eccentric exercise based on the previous literatures .
skeletal muscle comprises contractile myofibrils and ecm ( gao et al . , 2008 ) .
ecm is involved in the maintenance of normal cell physiology , including structural integration , proliferation , differentiation , and apoptosis ( gattazzo et al . , 2014 ) .
furthermore , ecm supports the structure of the skeletal muscle by enhancing mechanical stress and plays a critical role in force transmission ( koskinen et al . , 2002 ) .
mmps are calcium and zinc - dependent proteolytic enzymes , also known as matrixins ( nagase et al . , 2006 ) .
about 24 mmps have been identified in humans ( klein and bischoff , 2011 ) ; these 24 mmps can be subdivided into membrane - type mmps and soluble - type mmps ( barnes et al . , 2009 ) .
mmp collagenases ( mmp-1 , -8 , -13 , and -18 ) break down interstitial collagen types i , ii , and iii and mmp gelatinases ( mmp-2 and -9 ) degrade denatured collagen type iv , vii , and x ( monaco et al . ,
collagen type iv is a key component of basement membranes as well as cell arrangement in tissues ( carmeli et al . , 2004 ) .
mmp can degrade ecm alone or in combination with the plasminogen / plasmin system to facilitate the migration of inflammatory and myogenic cells , such as satellite cells , from ecm to the site of injury ( mann et al .
during the process of ecm degradation , several cytokines and growth factors are also released to regulate the proliferation and differentiation of the migrated cells ( lu et al . , 2011 ) .
this process is required for the remodeling of the tissue and is crucial for maintaining skeletal muscles in a normal state . an in vitro study showed that the migration of satellite cells to the injury site is a key process in the regeneration of skeletal muscles and that ecm degradation can be a pivotal component of satellite cell migration and regeneration ( chen and li , 2009 ) . in particular , mmp-2 and -9 show biological activities mostly in skeletal muscles because their primary substrate is a key component of ecm in skeletal muscles ( sternlicht and werb , 2001 ) .
mmp-2 and -9 have been reported to be expressed in different stages ; mmp-2 may be activated simultaneously with the regeneration of muscle fibers , whereas mmp-9 may be expressed in association with the early inflammatory response and activation of satellite cells ( agren , 1994 ; carmeli et al . , 2004 ; kherif et al . , 1999 ) . taken together ,
these findings suggest that mmp-2 and -9 are involved in not only inflammatory responses but also ecm remodeling and muscle regeneration .
clinical studies on pathophysiology have reported that hyperactivation of mmp facilitates the infiltration and metastasis of tumor cells , which may induce carcinogenesis , and may cause chronic diseases , such as fibrosis , rheumatoid arthritis , and parkinson s disease ( ramezani and shamsara , 2015 ) .
a 1:1 ratio between mmps and timps prevents hyperactivation of mmps ( visse and nagase , 2003 ) .
there are four timp isoforms ( i.e. , timp-1 , -2 , -3 , and -4 ) , which show tissue - specific , constitutive , or inducible expression depending on the transcriptional level .
timp-1 is widely expressed in many mammalian tissues induced by growth factors , phorbol esters , and cytokines .
finally , timp-4 has tissue - specific functions , commonly expressed in the heart , kidneys , lungs , testes , and brain , but rarely expressed in muscles and ovaries ( murphy , 2011 ) . among the four timp isoforms , timp-1 and -2
have been reported to be significantly upregulated in eccentric exercise - induced muscle damage ( koskinen et al . , 2002 ) or rotator cuff tears ( castagna et al . , 2013 )
eccentric exercise induces muscle damage , increases mobilization of inflammatory cells ( clarkson and hubal , 2002 ) . as shown in fig .
1 , ecm responds to forceful mechanical stress , such as high - intensity eccentric exercise ( gao et al . , 2008 ; kovanen , 2002 ; mackey et al . ,
2004 ) , during which ecm is degraded as muscle fiber damage occurs ( stauber , 2004 ) .
additionally , mmp and timp responses occur simultaneously ( mackey et al . , 2004 ) .
mmps , specifically mmp-2 , are downregulated during low - intensity exercise , but upregulated in high - intensity exercise ( carmeli et al . , 2005 ) ;
some studies have reported that the expression and activation of mmp-2 or -9 are increased following high - intensity eccentric exercise ( koskinen et al .
koskinen et al . ( 2001a ) reported that eccentric exercise via downhill running results in acute increases in mmp-9 , timp-1 , and the mmp-2/timp-2 complex .
2004 ) reported that high - intensity eccentric exercise on a knee extensor results in an increase in mmp-9 until eight days after exercise and an increase in timp-1 for four days after exercise and continued to increase up to 14 days .
( 2007 ) found that eccentrically biased electrical stimulation increases mmp-2 , timp-1 , and timp-2 expression while koskinen et al .
( 2002 ) suggested that the electrical stimulation in mice significantly increases the mrna expression and activation of mmp-2 and -9 between 4 and 7 days following exercise .
muscle damage may lead to an increase in the number of leukocytes and prostaglandin concentrations ( prisk and huard , 2003 ) .
leukocytes include inflammatory cells , such as neutrophils and macrophages ( tidball , 2005 ) ; prostaglandin facilitates inflammatory responses and is released by high - intensity muscle contractions ( karamouzis et al . , 2001 ) .
mmp-9 is synthesized by leukocytes ( murphy et al . , 1989 ) , and prostaglandin stimulates the expression of mmp-2 and -9 in human t cells ( goetzl et al . , 1996 ) .
( 2002 ) have microscopically observed the infiltration of inflammatory cells in injured muscles with increased mmp-9 levels following eccentric muscle contractions .
in addition , some studies have reported that ecm degradation assists the migration and invasion of immune cells into the injured muscle ( carmeli et al . , 2004 ; klein and bischoff , 2011 ) . parks and
mecham ( 2011 ) suggested that mmp is a biological marker representing the inflammatory response .
koskinen et al . ( 2001a ) reported that after downhill running , timp-1 is expressed in the early stages of muscle damage , whereas timp-2 is expressed during the later stages of muscle damage .
timp-1 is intimately related to mmp-9 , and timp-2 binds strongly to mmp-2 ( goldberg et al . , 1989 ) .
some studies have shown that the activity levels of timps correspond to changes in the activity of mmp-2 and -9 ( overall et al . , 1991 ; singh et al . , 2000 ) . as previously described , mmp-2 is usually activated during the early stages of muscle regeneration , whereas mmp-9 is typically activated during the early stages of the inflammatory response .
thus , mmp-9 and timp-1 may interact during the early stages of exercise - induced muscle damage , and mmp-2 and timp-2 may interact during the later stages of muscle damage ( muscle regeneration ) .
in essence , mmp-9/timp-1 and mmp-2/timp-2 have antagonistic effects in the inflammatory response following eccentric exercise and regulate the degradation and remodeling of ecm . however , there is little evidence to support the relationship between posteccentric exercise mmp and timp responses and inflammatory cells .
( 2016 ) reported that acute eccentric exercise reduces the levels of mmp-2 and -9 up to 48 hr following exercise and interleukin-6 levels were also reduced .
these data suggest that mmp-2 and -9 levels may be altered in parallel to changes in the expression of inflammatory factors
( 2016 ) studied obese women , whereas most previous studies of eccentric exercise have been conducted in healthy subjects .
obese people are known to have an imbalance in inflammatory factors ( jung and choi , 2014 ) .
( 2016 ) also demonstrated that exercise may result in anti - inflammatory responses by reducing mmp-2 and -9 levels because obese individuals maintain a high inflammatory response , even at rest , as compared with healthy subjects .
therefore , future studies should also examine changes in and the relationships among mmp-2 , -9 , and inflammatory factors following eccentric exercise in healthy subjects .
nonetheless , some studies have suggested that eccentric exercise does not induce significant mmp or timp responses , and some researchers have argued that there is no association between the two .
( 2014 ) reported that although mmp-9 is significantly increased after downhill running , the change is not substantial .
( 2011 ) reported that there were no changes in mmp-9 and timp-1 responses at all time points following eccentric exercise using an elbow flexor model . unlike prior studies , which mainly used the downhill running model , madden et al .
the elbow flexor model is known to induce greater muscle damage than the downhill running model ( jamurtas et al . , 2005 ) . despite such differences in exercise models
, there were no changes in mmp-9 after eccentric exercise using an elbow flexor model .
this result may indicate that eccentric exercise using an elbow flexor model does not involve the muscles sufficiently for mmp-9 response ( madden et al .
( 2011 ) suggested that differences in the exercise protocol may also explain these discrepancies .
as shown in table 1 , many studies consistently found mmp and timp responses following downhill running and knee extensor models ( koskinen et al . , 2001a ; mackey et al . ,
likewise , mmp-9 levels seems to show greater increase during whole body exercise or exercise with large muscle groups involved , such as marathon and cycling compared to local exercise with small volume of muscles involved such as arm curls ( rullman et al .
2006 ) . this may be supported by differences in ecm composition , turnover , systemic vasculature , and local clearance between upper and lower muscles ( madden et al . , 2011 ) ; however , it has yet to be scientifically verified . since the study conducted by madden et al .
( 2011 ) remains the only study using an elbow flexor model , additional studies using similar models are required to produce meaningful conclusions .
eccentric exercise induces muscle damage and increases ecm degradation , during which mmps and timps are also activated .
these two enzymes maintain the homeostasis of ecm via antagonistic effects in muscle degradation and remodeling .
to date , mmp and timp responses have mostly been studied in animals or patients with chronic illnesses .
furthermore , studies on muscle damage have also been conducted by inducing damage by freeze exposure or drug injections rather than exercise .
although some studies have examined posteccentric exercise mmp and timp responses , only animal studies have produced clear mmp and timp responses following eccentric muscle contraction .
more studies on human subjects , particularly using elbow flexor models , should be conducted and posteccentric exercise inflammatory responses or factors related to muscle regeneration should be measured in addition to mmp and timp responses .
in addition , because ecm degradation may reduce force transmission , studies should analyze the association between posteccentric exercise mmp or timp levels and reduction of maximum voluntary muscle contraction .
 high - intensity eccentric exercise is known to induce muscle damage leading to inflammatory responses and extracellular matrix ( ecm ) degradation . 
 these degradation processes involve enzymes such as matrix metalloproteinases ( mmps ) and tissue inhibitor of metalloproteinases ( timps ) . 
 mmps are calcium and zinc - dependent proteolytic enzymes that play a role in ecm degradation and recruitment of inflammatory and myogenic cells into the damaged site . in contrast , timps inhibit mmp - induced ecm degradation to maintain normal homeostasis in ecm . 
 recently , several studies have examined the process of muscle remodeling and the roles of ecm , mmps , and timps in exercise - induced muscle damage . however , the results of these studies are not inconsistent . in the present mini - review 
 , we will discuss the responses of mmp and timp to eccentric exercise based on the literature review . 
INTRODUCTION
MATRIX METALLOPROTEINASE IN SKELETAL MUSCLE
TISSUE INHIBITOR OF METALLOPROTEINASE IN SKELETAL MUSCLE
MATRIX METALLOPROTEINASE AND TISSUE INHIBITOR OF METALLOPROTEINASE RESPONSES TO ECCENTRIC EXERCISE
CONCLUSIONS