muscle is a heterogeneous tissue , containing cells with different contractile properties , metabolic profiles , and fatigue resistance .
much of this diversity is correlated with the myosin heavy chain ( mhc ) isoform expressed by the cell .
small mammals express nine mhc isoforms of which four , type i or  , type iia , type iix , and type iib , are expressed in adult limb muscles ( ennion et al .
the type iib isoform is not found in the limb muscles of large mammals , including humans .
human muscle fibers can be categorized into three fiber types : type i , iia , and iix ( ennion et al . , 1995 ; smerdu et al . ,
these isoform can also be co - expressed , resulting in hybrid fiber types : type i / iia , and type iia / iix or even type i / iia / iix ( caiozzo et al .
, 2003 ; pette and staron , 2001 ) . typical characteristics of fiber types are force production , and shortening velocity .
type iia or iix fiber produce higher force and contract faster than type i fibers , whereas type i fibers appear to be more fatigue resistant than other fiber types .
type iix fiber contract and relax slightly faster than type iia fibers , but both are faster than type i fiber .
as well known , an eccentric contraction is much more likely to injury a muscle compared to an isometric contraction or a contraction in which the force producing muscle shortens ( allen , 2001 ; faulkner et al . , 1993 ; lieber and friden , 2002 ; proske and allen , 2005 ; warren et al . ,
it is also generally accepted that fast muscle fibers are more susceptible to eccentric contraction than slow muscle fibers ( friden et al . , 1983
; jones et al . , 1986 ; lieber and friden , 1988 ; warren et al . , 1994 )
this idea is based on histological and functional experiments performed on human and animal models .
however , a critical appraisal of this body of work shows that the evidence supporting the idea that fast muscle fibers are more susceptible to eccentric injury is far from complete or conclusive .
therefore , in this review the detail limitation of previous work on distinct susceptibility on mhc isoform will be discussed first , and then recent work on differential susceptibility of mhc heterogeneity will be reviewed .
studies on humans have reported a greater susceptibility of fast - twitch fibers to damage ( asp et al . , 1998 ; friden et al . , 1983
however , these studies have used indirect methods to quantify the muscle injury such as histological markers of damage ( friden et al . , 1983 ) or the plasma creatine kinase ( ck ) concentration ( jones et al . , 1986 ) .
plasma ck concentration is frequently used as an index of the muscle damage after eccentric contraction .
however , no significant correlation was observed between ck concentration and muscle strength ( friden and lieber , 2001 ) . another study investigated muscle glycogen content after eccentric exercise , and it revealed type ii fibers were predominantly recruited ( asp et al . , 1998 ) .
thus the authors concluded a selective effect of eccentric contractions on type ii fiber but it could not be readily accepted that the glycogen content represents the susceptibility of muscle structure and functional to damage .
functional approaches performed on isolated mouse muscle ( soleus and extensor digitorum longus ( edl ) ) are limited by fiber type heterogeneity and muscle architectural differences .
for instance , mouse soleus muscles are not constituted with only slow fiber types , and mouse edl muscle express an extra mhc isoform , type iib , which is not founded in human limb muscle ( ennion et al . , 1995 ;
furthermore , its slow type i mhc isoform has a faster velocity than the human slow type i mhc ( widrick et al . , 1997 ) .
thus , these species differences could confound generalization of animal data to humans . also , the differences of muscle architecture between mouse soleus and edl muscle resulted in the differentiation of applied strain amount to each muscle , due to differences in the fiber length to muscle length ratios of these muscles ( warren et al . , 1994 ) .
studies using single muscle fibers , obtained from animals report that muscles comprised of predominantly fast fibers are preferentially damaged ( brockett et al . , 2002 ;
friden and lieber , 1992 ; lieber and friden , 1988 ; lynch et al . , 2008 ; macpherson et al . , 1996 ;
only three of these studies have directly examined muscle fiber function : two studies examined fibers from the predominately slow soleus and the predominately fast edl of the rat ( lynch et al . , 2008 ; macpherson et al . , 1996 ) , and another study examined fibers from normal and congenitally clefted goat palates ( rader et al . , 2007 ) .
as discussed above , small mammals and humans do not express all of the same mhc isoforms .
sarcomere heterogeneity after eccentric contractions was also measured with fiber type identification by sodium dodecyl sulfate polyacrylamide gel electrophoresis ( sds - page ) ( patel et al . , 2004 ) .
however , they used the pooled fiber bundles from the frog tibialis anterior muscle , which is comprised of two equal part of fastest amphibian muscle fiber type ( lutz et al . , 1998 ) .
brockett ( brockett et al . , 2002 ) also studied the vulnerability of different motor units that consisted of mixed fiber types using the cat muscle without identifying the fiber types .
none of these studies examined mhc isoform content and function in the same fibers , making it difficult to draw conclusions about damage to individual fiber types . although most studies show greater susceptibility of fast - twitch fibers , a few studies report that slow - twitch , or type i fibers , were selectively damaged during eccentric contractions
1983 ) showed that the deeply embedded slow - twitch fibers were predominantly damaged after downhill running compare to level running .
however , downhill running may preferentially recruit the slow fiber type , and this may obscure which type is actually more susceptible .
another study indicated the increased fragment rate in slow - twitch skeletal mhc through magnetic resonance imaging ( mair et al . , 1992 ) , and plasma creatine kinase ( ck ) concentration , which is not a highly correlated index of muscle damage .
even though there is no conclusive mechanism yet , several potential mechanisms were proposed to explain the greater vulnerability of fast - twitch fibers .
one proposed mechanism was that fast - twitch fibers fatigued faster than slow - twitch fiber , and the fast - twitch fibers stay in rigor binding stage during cross - bridge cycle due to impaired atp regeneration , which results in mechanical damage as these rigor fibers are stretched ( friden and lieber , 1992 ) .
however , this hypothesis does not hold up because studies report that fatigued muscle is less susceptible to damage or fatigue has no effect ( choi and widrick , 2009 ; friden and lieber , 1992 ; mair et al . , 1996 ; morgan et al . ,
2004 ) and other studies support the fatigued muscle is more resistible to eccentric - induced muscle injury ( nosaka and clarkson , 1997 ) .
it has been suggested that the ultrastructural differences between type i and type ii fibers explain the greater vulnerability of fast - twitch fibers to eccentric - induced muscle damage .
fast - twitch fibers have narrower z - lines compared to slow - twitch fibers ( friden et al . , 1983 ) , which reflect fewer attachments for thick and thin filaments ( yamaguchi et al . , 1985 ) .
type ii fibers contain smaller isoforms of the sarcomeric proteins myomesion and nebulin , which play a role in sarcomere assembly ( agarkova et al .
therefore , relatively greater stress is applied to the cytoskeleton of fast fiber , resulting in a higher susceptibility to damage .
this phenomenon also confirmed from the reloaded human soleus fiber after 17 days of bed rest and spaceflight ( widrick et al . , 1999 ) .
he found that the fibers , have weak connections between sarcomeres were relatively weaker than fibers , have normal connection between sarcomeres , due to greater workload .
also , fast fibers express a lower molecular weight , and less elastic , titin isoform than slow fibers ( prado et al . , 2005 )
the less compliant titin in fast fibers may transmit greater stress during eccentric contractions ( horowits , 1992 ) .
accordingly , it is widely accepted that fast - twitch , or type ii fibers tend to be more vulnerable to eccentric - induced muscle injury ( byrne et al . ,
however , none of above studies has investigated the relationship between fiber mhc isoform content and its susceptibility to eccentric contraction using single fiber preparation , isolated from human muscle , with the identification of fiber type .
accordingly , it is clear that more data examining the relationship between fiber type expression and susceptibility after eccentric contraction are required . chemically skinned single muscle fiber preparations can avoid limitations of previous studies by allowing the investigator control over strain magnitude and velocity under standard experimental conditions of temperature , ionic strength and activating ca concentration .
the issue of fiber type heterogeneity can also be overcome by identification of mhc isoforms in the same of single muscle fiber segments used for the physiological assays .
there is a study that utilizes the single fiber approach to examine the differential susceptibility on mhc isoform ( choi and widrick , 2010 ) .
ca - activated skinned muscle fiber segments , prepared from healthy untrained young subjects ( 252 yr , n=10 ) were subjected to standardized an eccentric contraction , in terms of strain magnitude ( 25% of fiber length ) and lengthening velocity ( 50% of maximum shortening velocity ) .
maximal force was measured before and after a single eccentric or fixed - end contraction , and fiber mhc isoform contents were confirmed by gel electrophoresis .
a model was developed using multiple linear regression to describe how each of major fiber type populations present in human limb muscle responds to a single eccentric contraction , the best model reveals a fiber type independent factor ( pre - treatment force ) and a fiber type dependent factor ( mhc expressions ) to the damage process .
regardless of fiber type , fiber generating greater pre - eccentric specific force showed greater post - eccentric force deficits . when this pre - treatment force was controlled , fiber expressing type i or iia mhc had identical force change to the eccentric contraction , whereas fiber co - expressing the type iia and iix mhc isoforms showed 3-folder greater force deficit .
these results could be interpreted as evidence that the fastest mhc isoforms , in this case type iix , were associated with greater damage .
however , an equally valid interpretation would be that the co - expression of multiple mhc isoforms within the same fiber is the critical factor .
however , a limitation of the skinned fiber approach is that fibers are studied in an artificial milieu ( although one thought to represent the intracellular milieu ) .
in addition , the skinning process may remove or allow efflux of structural ( e.g. dystrophin ) or enzymatic ( e.g. calpain ) proteins that may be involved in the damage process .
finally , fibers are maximally activated where in vivo , different fiber types may be differentially recruited by the nervous system , altering their apparent susceptibility to injury .
therefore , additional studies need to address the response of living cells to in vivo eccentric exercise .
while most studies conclude that type ii fibers are more susceptible to eccentric - induced muscle injury , these finding are based on indirect measures of damage , conducted on muscles instead of fibers , and if conducted on fibers , have not confirmed mhc isoform context by gel electrophoresis which provide a more accurate determination of the fiber types including hybrid fiber ( glaser et al . , 2010 ; pandorf et al . ,
since most muscles are heterogeneous in the fiber type composition , whole muscle or motor unit studies can not effectively evaluate changes of function occurring in type i and type ii fibers following eccentric contractions .
however , recent single muscle fiber study found a single eccentric treatment ( 25% strain with 50% lengthening velocity ) resulted in 9 kn / m ( 8.1% ) and 12 kn / m ( 9.8% ) of force drop compare to pre - treatment force for fibers expressing a single mhc isoform ( i and iia , respectively ) . however , hybrid fibers containing iia and iix mhc isoform showed 3-folders greater force deficit ( 38 kn / m , 28.4% ) than either type i or type iia fibers .
these results indicate that human fast hybrid fibers ( iia / iix ) are further sensitive to a standardized in vitro eccentric contraction .
 based on myosin heavy chain ( mhc ) isoform , human skeletal muscle fibers can be categorized into three fiber types , type i , iia , iix fibers , and each fiber type has different characteristics . 
 typical characteristics are difference in force production , shortening velocity , and fatigue resistance . 
 when the muscle is contract and stretched by a force that is greater than the force generated by the muscle , contraction - induced muscle damage frequently occurs . 
 several experimental models involving both human and animal have considered the susceptibility of different muscle fiber type and part of muscles to eccentric induced muscle damage . 
 general consensus is a greater susceptibility of fast - twitch fiber or type ii fiber to damage following eccentric contractions . 
 however , the results from these previous efforts were not enough to conclude the susceptibility between each individual fiber types after eccentric contraction . 
 therefore , the purpose of this review is to explore detail limitation and interpretation of previous studies , and review the recent study that eliminated the prior limitations , such as strain magnitude , lengthening velocity , fiber type heterogeneity , and muscle architecture issue . 
INTRODUCTION
PREVIOUS STUDIES IN DISTINCT SUSCEPTIBILITY ON MHC ISOFORM
POTENTIAL MECHANISM OF PREFERENTIAL DAMAGE TO FAST TWITCH MUSCLE AFTER ECCENTRIC CONTRACTION
RECENT STUDIES IN DISTINCT SUSCEPTIBILITY ON MHC ISOFORM
CONCLUSIONS