11
Muscle degeneration in rotator cuff tears Dominique Laron, MD a , Sanjum P. Samagh, MD, MS a , Xuhui Liu, MD b , Hubert T. Kim, MD, PhD a,b , Brian T. Feeley, MD a, * a Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, USA b Veterans Affairs Hospital, San Francisco, CA, USA Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- and medium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown to develop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologic changes have been found to be independent predictors of failed surgical repair with poor functional outcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an under- standing of the changes that occur within the cuff muscles themselves. The purpose of this review is to summarize the molecular pathways behind muscular degeneration and emphasize new findings related to the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understanding these molecular pathways will help guide further research and treatment options that can aim to alter expression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears. Level of evidence: Review Article. Ó 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. Keywords: Rotator cuff tear; muscle atrophy; fatty infiltration Introduction Rotator cuff tears (RCTs) are extremely common injuries and represent the most common muscle-tendon tear in patients. As the rotator cuff ages, it becomes susceptible to degener- ative changes, which can lead to shoulder dysfunction. Rotator cuff repair oftentimes works well in patients with small- and medium-sized tears; however, large and massive tears have been shown to develop muscle atrophy and fatty infiltration within the cuff muscles. Clinically, both muscle atrophy and fatty infiltration are independent predictors of failed surgical repair with poor functional outcomes. Understanding the pathophysiology of rotator cuff disease begins with an understanding of the molecular, physical, and clinical changes that occur within the cuff muscles. Unlike tendon degeneration, which has been a focus of study for many years, relatively few studies have evaluated the degenerative processes that occur within the muscles after an RCT. This article will review the basic science and molecular pathways behind muscular degeneration and detail new findings related to the clinical relevance of muscle atrophy and fatty infiltration in the setting of RCTs. Muscle structure and regulation of muscle size and atrophy Myocytes and extracellular matrix The harmful changes that occur after RCTs can be under- stood by examining the functional roles and molecular pathways that govern muscle cell structure. Muscle is *Reprint requests: Brian T. Feeley, MD, Department of Orthopaedic Surgery, University of California, San Francisco, 1500 Owens Dr, Box 3004, San Francisco, CA 94158, USA. E-mail address: [email protected] (B.T. Feeley). J Shoulder Elbow Surg (2012) 21, 164-174 www.elsevier.com/locate/ymse 1058-2746/$ - see front matter Ó 2012 Journal of Shoulder and Elbow Surgery Board of Trustees. doi:10.1016/j.jse.2011.09.027

Muscle degeneration in rotator cuff tears

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Muscle degeneration in rotator cuff tears

Dominique Laron, MDa, Sanjum P. Samagh, MD, MSa, Xuhui Liu, MDb,Hubert T. Kim, MD, PhDa,b, Brian T. Feeley, MDa,*

aDepartment of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, USAbVeterans Affairs Hospital, San Francisco, CA, USA

Rotator cuff tears are among the most common injuries seen by orthopedic surgeons. Although small- andmedium-sized tears do well after arthroscopic and open repair, large and massive tears have been shown todevelop marked muscle atrophy and fatty infiltration within the rotator cuff muscles. These pathologicchanges have been found to be independent predictors of failed surgical repair with poor functionaloutcomes. To understand the pathophysiology of rotator cuff disease, we must first develop an under-standing of the changes that occur within the cuff muscles themselves. The purpose of this review is tosummarize the molecular pathways behind muscular degeneration and emphasize new findings relatedto the clinical relevance of muscle atrophy and fatty infiltration seen with rotator cuff tears. Understandingthese molecular pathways will help guide further research and treatment options that can aim to alterexpression of these pathways and improve outcomes after surgical repair of massive rotator cuff tears.Level of evidence: Review Article.� 2012 Journal of Shoulder and Elbow Surgery Board of Trustees.

Keywords: Rotator cuff tear; muscle atrophy; fatty infiltration

Introduction

Rotator cuff tears (RCTs) are extremely common injuries andrepresent the most common muscle-tendon tear in patients.As the rotator cuff ages, it becomes susceptible to degener-ative changes, which can lead to shoulder dysfunction.Rotator cuff repair oftentimes works well in patients withsmall- and medium-sized tears; however, large and massivetears have been shown to develop muscle atrophy and fattyinfiltration within the cuff muscles. Clinically, both muscleatrophy and fatty infiltration are independent predictors offailed surgical repair with poor functional outcomes.Understanding the pathophysiology of rotator cuff disease

uests: Brian T. Feeley, MD, Department of Orthopaedic

sity of California, San Francisco, 1500 Owens Dr, Box

isco, CA 94158, USA.

ss: [email protected] (B.T. Feeley).

ee front matter � 2012 Journal of Shoulder and Elbow Surgery

.2011.09.027

begins with an understanding of the molecular, physical, andclinical changes that occur within the cuff muscles. Unliketendon degeneration, which has been a focus of study formany years, relatively few studies have evaluated thedegenerative processes that occur within the muscles after anRCT. This articlewill review the basic science andmolecularpathways behind muscular degeneration and detail newfindings related to the clinical relevance of muscle atrophyand fatty infiltration in the setting of RCTs.

Muscle structure and regulation of muscle sizeand atrophy

Myocytes and extracellular matrix

The harmful changes that occur after RCTs can be under-stood by examining the functional roles and molecularpathways that govern muscle cell structure. Muscle is

Board of Trustees.

Figure 1 A sarcomere, the basic unit of a muscle cell. It iscomposed of multiple nuclei with myofibrils that are thecontractile units of the muscle. Actin makes up the thin filament,and myosin make up the thick filament. (Reprinted with permis-sion from Tomioka T, Minagawa H, Kijima H, Yamamoto N,Abe H, Maesani M, et al. Sarcomere length of torn rotator cuffmuscle. J Shoulder Elbow Surg 2009;18:955-9. doi:10.1016/j.jse.2009.03.009.)

Muscle degeneration in rotator cuff tears 165

a unique and dynamic organ that is adaptive and respondsto mechanical loads. It is dependent on a vast set ofsignaling pathways that include growth hormones, signaltransduction pathways, and importantly, mechanicalsignals. Muscles respond to growth stimuli by increasingprotein synthesis and developing a larger mass withouta significant increase in myocyte number.

Unlike most other cells in the human body, the myo-cyte is a multinucleate cell that often contains over 100nuclei in its mature state. Myocytes sit within an extra-cellular matrix of myofibrils, which are long chains ofsarcomeres, to form myocyte contractile units (Fig. 1). Inaddition, there are a number of other cells, includingfibroblasts, blood vessel endothelium cells, and muscleprogenitor or stem cells (subtyped into satellite cells andmuscle special cells), that form the body of the muscle.Muscle satellite cells, which are thought to be derivedfrom pericytes,16 have recently been found to be one ofthe primary progenitor cells in skeletal muscle; theymerge into adjacent myocytes to replace dying myocytenuclei.80 Satellite cells can also form new myocytes,a process that is seen mainly in muscle development andregeneration.12 Myofibers are connected to each otherthrough the extracellular matrix (ECM), which hasa central role in cell communication, transduction ofmechanical force signals, and regulation of muscledifferentiation, growth, repair, and remodeling. The ECMstores various growth factors and other bioactive mole-cules, including active and inactive proteases that can bereleased and activated by specific signal pathways thathelp modulate the changes seen in muscle.46,69

During the development of muscle atrophy, there issignificant remodeling of the ECM that includes increasedcollagenous connective tissue (fibrosis). A group of zinc- orcalcium-dependent proteinases, called matrix metal-loproteinases (MMPs), is believed to play an important roleof ECM remodeling in skeletal muscle. These enzymesalter protein expression within the cell to stimulate tissueremodeling.2 Recent studies have shown significantly

increased expression of MMP-2, MMP-9, and MMP-13 inmuscle atrophy.81,82 These MMPs have been implicated intendon degeneration and tissue degradation in other diseasestates, and their roles in muscle changes have recently beenevaluated. MMPs have been found to be involved inincreasing atrophy in a rat and rabbit model of muscleatrophy.4,19,49 MMP-2, MMP-9, and MMP-13 are thoughtto be involved in the transformation and morphogenesis ofcells as well as degradation in both pathologic and non-pathologic states.21,81 For example, Rodeo and colleagues81

found that MMP-1, MMP-9, and MMP-13, of which MMP-1and MMP-13 are collagenases, have increased expressionin the supraspinatus tendon after it has been torn. Theirpresence indicates a cell-mediated tendon degradation thatcould possibly lead to the biomechanical instability seen inRCTs.81

Molecular regulation of muscle size andprotein synthesis

Although new mature myocytes are rarely added to muscle,the muscle remains a dynamic structure that must respondto changes in daily demand and functional requirements.Regulation of muscle size is determined at the cellular leveland is controlled by the magnitude of protein synthesis.These are complex and multifaceted pathways that areresponsible for both protein synthesis and breakdown.Mechanical signals, growth hormones, insulin-like growthfactor (IGF), and nuclear factor kappa B (NF-kB) havebeen implicated in regulating muscle size.48 Alterations inthese signal transduction pathways can either increase ordecrease muscle size, dependent on the regulation of thesepathways.

The majority of animal model studies evaluating muscleatrophy in RCTs have focused on muscle atrophy genesthat alter the expression of protein degradation (Fig. 2). Theubiquitin-proteasome system is the primary regulator ofprotein breakdown that provides a mechanism for selectivedegradation of regulatory and structural proteins. Ubiquitinligases are the key enzymes in this system.47 It has beenhypothesized that NF-kB has a central role in the devel-opment of muscle atrophy through three mechanisms53: (1)NF-kB can augment the expression of several proteins ofthe ubiquitin-proteasome system involved in the degrada-tion of specific muscle proteins; (2) NF-kB can increase theexpression of inflammation-related molecules that directlyor indirectly promote muscle wasting; and (3) NF-kB caninterfere with the process of myogenic differentiation thatmay be required for regeneration of atrophied skeletalmuscles.28

NF-kB and forkhead transcription factor (FOXO) areresponsible for the regulation and increased expression ofatrophy-related proteins.75,76 Two inducible E3 ubiquitinligases, atrogin-1 (also known as MAFbx) and musclering finger protein 1 (MuRF1), have been identified asenzymes responsible for the degradation of the bulk of

Figure 2 Diagram of ubiquitin-proteasome protein degradation system. (Reprinted with permission from Murton AJ, Constantin D,Greenhaff PL. The involvement of the ubiquitin proteasome system in human skeletal muscle remodeling and atrophy. Biochim BiophysActa 2008;1782:730-43. doi:10.1016/j.bbadis.2008.10.011.)

166 D. Laron et al.

skeletal muscle in multiple different atrophic conditionsthrough denervation and hindlimb-suspension animalmodels.31,35,51,52,79,94 Schmutz et al74 showed that thesefactors are also upregulated in patients with chronicsupraspinatus tears. These data support the hypothesis thatNF-kB, MuRF1, and atrogin-1 all have an important rolein the protein degradation found in the development ofrotator cuff muscle atrophy47 (Fig. 3).

Given that muscle responds to mechanical loading, it isnot surprising that mechanical load can alter muscularprotein regulation. Studies over the last decade have shownthat muscle is able to transfer mechanical load signaling tothe upregulation of muscle protein synthesis. Multiplestudies have suggested that the Akt-mammalian target ofrapamycin (mTOR) pathway plays a central role in thesignal transduction network controlling musclesize.7,8,59,64,83 Phosphorylation of Akt inhibits FOXOtranslocation, thereby inhibiting activation of atrogin-1 andMuRF protein degradation.59,64 These studies have beenperformed in hindlimb-suspension models of muscleatrophy and only recently have been studied in a rotatorcuff model. By use of a rat model of massive RCTs, wehave shown that this pathway demonstrates alteredexpression.55 We found increased phosphorylation ofmTOR and Akt, leading to increased expression of atrophy-related molecules and increased muscle atrophy. Thispathway can also be regulated pharmacologically through

inhibitors and represents interesting potential targets formodulating muscular atrophy after a rotator cuff repair.

Fatty infiltration and muscle injury

RCTs lead to degeneration of the cuff muscles with thedegree of muscular degeneration and fatty infiltrationincreasing with the size of the tear. This is seen in elderlypopulations with massive tears: rotator cuff muscles oftenshow marked muscle atrophy and fatty infiltration observedby both computed tomography and magnetic resonanceimaging (MRI) and on visual inspection at the time ofsurgical intervention (Fig. 4). Histologic lipid stains ofmuscle after chronic and massive RCTs show high amountsof fat that correlate with levels of fatty infiltration seen onradiographic imaging. Goutallier et al43 proposed gradingfatty infiltration based on the ratio of fat to muscle (Table I).This grading system is important because the level of fattyinfiltration significantly increases with tear severity. Thissystem also correlates the decrease in muscle function seenafter massive tears with the levels of fatty infiltration at thetime of repair.20,43 Patients graded with pathologic levels offatty infiltration clinically exhibit a limited range of activeexternal rotation compared with those graded 2 orless.20,42,43 The quantity of fatty infiltration is important notonly because of its effects on decreased muscle function but

Figure 3 Akt signaling pathway in skeletal muscle. Akt is activated via phosphorylation and influences the anabolic and catabolic eventsin muscle. (Adapted with permission from Murton AJ, Constantin D, Greenhaff PL. The involvement of the ubiquitin proteasome system inhuman skeletal muscle remodeling and atrophy. Biochim Biophys Acta 2008;1782:730-43. doi:10.1016/j.bbadis.2008.10.011.)

Figure 4 Structural changes seen in rotator cuff muscle. (A) Intact rotator cuff. (B) Shoulder with RCT. The muscle fibers appear to beshortened, with muscle atrophy and fatty infiltration occurring at the molecular level. (Reprinted with permission from Tomioka T,Minagawa H, Kijima H, Yamamoto N, Abe H, Maesani M, et al. Sarcomere length of torn rotator cuff muscle. J Shoulder Elbow Surg2009;18:955-9. doi:10.1016/j.jse.2009.03.009.)

Table I Grading of fatty infiltration in rotator cuff muscles

Goutalliergrade

Muscle description (based on computedtomography scan)

0 Completely normal muscle1 Some fatty streaks2 Amount of muscle is greater than fatty infiltration3 Amount of muscle is equal to fatty infiltration4 Amount of fatty infiltration is greater than muscle

Muscle degeneration in rotator cuff tears 167

also because there is a degree of fatty infiltration that can beirreversible, even after repair.

Despite the importance of fatty infiltration in surgicaloutcomes of rotator cuff repairs, little is known about theunderlying etiology of this process. Understanding the

molecular pathways responsible for fatty infiltration will beimperative to determine potential pharmacologic interven-tions that can reverse these degenerative processes after RCTs.One of the central regulators of adipogenesis is peroxisomeproliferatoreactivated receptor gamma (PPARg); thisreceptor is a ligand-activated transcription factor that plays animportant role in controlling gene expression in multiplephysiologic processes.70,71 It was initially characterized asa central regulator of developing adipose cells but has nowalsobeen implicated in the control of cell proliferation, macro-phage function, and immunity.37,84 PPARg is considered thedominant or ‘‘master’’ regulator of adipogenesis inducedduring the differentiation of preadipocytes into adipo-cytes.24,37,50,87 It has been shown thatPPARg is bothnecessaryand sufficient for fat cell differentiation.58,70,71

Figure 5 MRI scan of a patient with grade 2 fatty infiltration of the infraspinatus muscle with an associated supraspinatus tear. (A and B)Fatty infiltration in infraspinatus muscle (white outline). (C) Retraction of supraspinatus tear to the level of the glenoid (white arrow). (D)Supraspinatus tear (black arrows) with an intact infraspinatus tendon near its attachment (white arrows). (Reprinted with permission fromCheung S, Dillon E, Tham SC, Feeley BT, Link TM, Steinbach L, et al. The presence of fatty infiltration in the infraspinatus: its relationwith the condition of the supraspinatus tendon. Arthroscopy 2011;27:463-70. doi:10.1016/j.arthro.2010.09.014.)

168 D. Laron et al.

It has been postulated that denervation of the supra-spinatus also causes fatty changes within the muscle.However, even in the setting of an intact nerve, it hasbeen found that the supraspinatus and infraspinatus canundergo fatty infiltration. In a recent study, Cheunget al20 found that substantial fatty infiltration of theinfraspinatus can be seen even in the absence of aninfraspinatus tear if a supraspinatus tear is present.Moreover, the amount of fatty infiltration into the infra-spinatus was correlated with the degree of tear andatrophy in the supraspinatus20 (Fig. 5). The studysuggests that the cause for this fatty infiltration may bethe effect that the supraspinatus tear has on the supra-scapular nerve (SSN), which innervates both the supra-spinatus and infraspinatus muscles.20,58

Massive RCTs associated with neuropathy and dener-vation of the muscle are likely due to traction on theSSN.58 However, it remains unclear which cellularmechanisms are responsible for the increase in fat afterthe development of an RCT. It is hypothesized that one ofthe stem cell populations that reside in adult skeletal

muscle (satellite cells, pericytes, muscle-derived stemcells, or muscle side population cells) are responsible forthis type of adipogenic differentiation, but this has notbeen proven. A recent study found a new subpopulation offibrogenic/adipogenic progenitor cells that reside inmuscle but are derived from a specific lineage.45 Trans-plantation of these cells into muscle undergoing fattyinfiltration resulted in the development of ectopic fatproduction. This did not occur with implantation intohealthy muscle, suggesting that the local environmentcontrols the fate of these cells. The fibrogenic/adipogenicprogenitor cells are found to be quiescent in healthymuscle but very active in damaged muscle, suggestinga potential novel cellular source for the development offatty infiltration after rotator cuff muscle injury.45

Although there are many factors that have been foundto induce adipogenic differentiation of muscle stem cells,including oxidative stress,26 aging,11 and muscle degen-eration,44 the specific pathways in the setting of RCTsremain largely unknown, and the cellular source of thesecells remains undefined.

Figure 6 Hematoxylin-eosin staining of rat (A) supraspinatus and (B) infraspinatus muscle at 2 and 6 weeks after injury via an RCT(tendon transection [TT]) (middle) or tendon transection with denervation of the muscle (TTþDN) (right). Left, Control muscle. Thereappears to be an increase in the intrafibrillar space between the muscle fibers and an increase in the numbers of cells within the intrafibrillarspace. Magnification �500. (Reprinted with permission from Liu X, Manzano G, Kim HT, Feeley BT. A rat model of massive rotator cufftears. J Orthop Res 2011;29:588-95. doi:10.1002/jor.21266.)

Muscle degeneration in rotator cuff tears 169

Beyond the molecular changes that occur in the rotatorcuff muscles after RCTs, morphologic changes mayaccount for some of the characteristic pathology seen inRCTs. Meyer et al63 showed changes in the pennation angleafter RCTs in a sheep model. They used electron micros-copy to exhibit normal muscle fibers with unalteredmyofibrillar structure, with concurrent increases of inter-stitial fat and fibrous tissue from 3.9% to 45.9%. Geometricmodeling showed that the increase of the pennation angleseparated the muscle fiber bundles and infiltrating fat cells

filled this space between the reoriented muscle fibers. Theauthors concluded that fatty infiltration is not as mucha degenerative process but rather is an obligatory rear-rangement of tissue after musculotendinous retractionresults in gross architectural changes. This study showedthat these changes can be reversible when tension isreturned to the muscle-tendon unit. This suggests thatrotator cuff repair may improve outcomes by decreasing thedegree of atrophy and fatty infiltration through mechano-spatial means.40

170 D. Laron et al.

Muscle fibrosis in setting of muscle atrophy

Skeletal muscle fibrosis is a pathologic hallmark in chronicmyopathies where myofibers are replaced by progressivedeposition of ECM proteins. This fibrosis is observed inmany of the muscular dystrophies as well as in the settingof injury and denervation.19 Progressive muscle fibrosisleads to smaller muscle fibers resulting in decreasedcontractility and function. Myofibroblasts exert a major rolein the onset of fibrosis as a result of differentiation ofmuscle progenitor cells during the regenerative process. Ina small animal model of RCTs, we have found increasedmuscle fibrosis after induction of a massive RCT56 (Fig. 6).

Transforming growth factor b (TGF-b) is a pleiotropiccytokine that plays a central role in many different processes,including promoting myofibroblast differentiation andcontributing to wound healing, and is a central factor infibrosis.90,91 TGF-b has been found to be a critical regulatorof fibrosis across many different organ systems.77 It inducesnormal scar formation, is involved in the development ofpulmonary and renal fibrosis, and has been found to regulategene expression in muscular fibrosis.18,36,38,54,78 Interest-ingly, recent studies have found that there is crosstalkbetween this pathway and Akt-mTOR in the development ofmuscle atrophy. Sartori et al72 found that TGF-b activationinduces muscle atrophy that is independent from MuRF1upregulation but partially dependent on the Akt-mTORpathway.17 No studies to date have evaluated the role ofTGF-b in rotator cuff muscle atrophy.

Previous animal model studies have also shownincreased muscle fibrosis in the setting of RCTs. Gerberet al40,41 showed an increase of connective tissue in a sheepmodel of chronic RCTs. Similarly, Fabis et al32 showed anincrease in interstitial volumes in a rabbit supraspinatustendon detachment model at 6 and 12 weeks after tendondetachment. On the basis of these animal models, it is clearthat fibrosis develops in the setting of RCTs, yet the clinicalconsequences of fibrosis are uncertain. Further studies thatevaluate the specific pathways that contribute to fibrosisand determine the clinical and functional significance ofthis fibrosis are vitally important to understand the effectsof muscle changes seen after RCTs.

Clinical consequences of muscle atrophy andfatty infiltration

Massive RCTs are especially debilitating to the patientbecause of the significant shoulder pain and weakness thatit causes. These patients have limited function of theirupper extremity as the laxity around the glenohumeral jointimpairs their ability to carry out even basic activities ofdaily living.22,61,67,88,89 Massive RCTs are worrisomebecause patients with massive RCTs have good clinicaloutcomes much less frequently compared with those withsmall RCTs after repair.

Massive RCTs can affect the entire glenohumeral joint,a fact that is often evident in a patient’s history. Typically,massiveRCTs initiallymanifest with a lengthy history of armpain, limitations in active motion, and pain that affectsactivities of daily living because of the inability to elevate thearm.6,30,33,66,93 Physical examination of patients with largeRCTs often shows atrophy of the supraspinatus and infra-spinatus muscles in their respective fossa. A joint effusioncalled the ‘‘geyser sign’’may be present,where synovial fluidfrom the glenohumeral joint escapes into the subacromialbursa, leading to obvious deformity of the shoulder andshoulder swelling.23 The humeral head may also appearsubluxated beneath the deltoid, especially in the case wherethe coracoacromial ligament has been previously resected(anterosuperior escape).57 Visible radiographic signs of RCTinclude cephalic migration of the humeral head. Abnormalcontact between the humeral head and acromion can lead to‘‘femoralization,’’ or rounding, of the greater tuberosity ofthe humerus and ‘‘acetabularization,’’ or concave erosion, onthe underside of the acromion.85 Superior glenoid erosion isalso common; this leads to decreased distance between theacromion and humerus, termed the acromiohumeral interval(AHI), on anteroposterior radiographs. The AHI has beenused in determining the severity of the RCT. Studies haveshown that the extent of the RCT and fatty infiltration isinversely related to the AHI.73 Additional imaging modali-ties, including computed tomography and MRI, are oftenuseful in confirming RCT, sometimes showing atrophy andfatty infiltration of the rotator cuff muscles.

Poor functional outcomes in patients undergoing a rotatorcuff repair are correlated to the atrophy and fatty infiltration ofthe supraspinatus and infraspinatus muscles.42,62,77 Bothatrophy and fatty infiltration have independently been shownto be related to poor functional outcomes after RCT repair;a certain degree of this degeneration is irreversible even aftersuccessful repair.86 Importantly, patients with massive RCTsthat show marked atrophy and fatty infiltration have poorerclinical outcomes than those who do not have these changes.Gladstone et al42 evaluated 38 patients prospectively afterrepair and found that although clinical outcome scoresimproved considerably, therewas a strong negative correlationbetween muscle quality and outcome results in most cases.Muscle atrophy and fatty infiltration were independentpredictors of American Shoulder and Elbow Surgeons scoresand Constant scores. The authors also found progression ofatrophy and fatty infiltration even in some cases of a successfulrepair. This study shows that the natural history of large tears isto progress to development of atrophy and fatty infiltration.This leads to poorer outcomes, likely because of the inelas-ticity and poor function of themuscle-tendon unit. Conversely,Burkhart et al13,15 found that repair in the setting of even grade3 or 4 fatty degeneration can lead to improvement in clinicalfunction as well as improvement in the amount of atrophy andfat present in the muscle in select cases. Previous studiesindicated that successful repair in cases of Goutallier grade 3or 4 fatty infiltration was not common; hence, the repair of the

Muscle degeneration in rotator cuff tears 171

RCTshouldbeperformedas quickly as possible to prevent thisirreversible damage to the rotator cuff.39 Nevertheless, repairat any stage, even in patients with massive RCTs and signifi-cant fatty infiltration and atrophy, will help re-establish a forcecouple of the rotator cuff.14 Significant functional improve-ment is seen in patients with massive tears who undergo evenpartial repair, and therefore, repair attempts are indicated inpatients to improve functional outcomes when feasible.

Role of denervation of rotator cuff and clinicalconsequences of nerve injury

Patients with a nerve injury to the SSN, with or withouta concurrent RCT, can also present with the advancedatrophy, fibrosis, and fatty infiltration observed in theseinjuries.42 In a patient with an RCT, the SSN is at increasedrisk for injury, particularly in its proximal region, becauseof the tension placed on the nerve.3,27,60,65,68 Patients withisolated SSN injury typically present similarly to thosewith RCTs. Physical examination shows pain localized inthe posterior and lateral aspects of the shoulder madeworse with overhead activities, cross-body adduction, andinternal rotation.27,68 If the injury is at the suprascapularnotch, the supraspinatus and infraspinatus will both presentwith muscle weakness. If the nerve is entrapped at thespinoglenoid notch, then only atrophy of the infraspinatusmuscle will be present on examination. Although atrophyof the muscles is not always present, studies have shownthat patients with an SSN injury have atrophy of one orboth muscles nearly 80% of the time.5 Radiographs andMRI are useful in assessing impingement, atrophy, andfatty infiltration associated with nerve injury.9,34,92

Studies in patients with massive RCTs have shownaltered electromyographic findings consistent with an SSNneuropathy. Costouros et al25 evaluated 26 patients withmassive RCTs with electromyogram/nerve conductionstudies to evaluate for the presence of peripheral neurop-athy. Of the 26 patients, 14 had evidence of a peripheralnerve injury; 7 had an isolated SSN injury. Interestingly, 6of the 7 patients who underwent repair of the rotator cuffshowed partial or full recovery of the SSN palsy. Thissuggests that traction indeed causes injury to the nerve butthat the nerve appears to have the ability to recover aftercuff repair. It has also been observed that in patients withisolated SSN neuropathies, changes develop that mimic theatrophy and fatty infiltration seen in the setting of a massiveRCT. SSN neuropathy is considered a rare condition, but inpatients with massive RCTs, this finding may prove to bemore common. In a recently published study, Boykin et al10

found that 42% of patients with massive RCTs showedchanges on electromyography that were consistent withSSN injury. There were abnormal motor unit actionpotentials (seen in 88% of these patients), with 33% ofpatients showing evidence of denervation. Denervation islikely more prevalent than clinically recognized, and we

should consider performing electrodiagnostic studies in thepreoperative period to further elucidate these effects. It isunclear at this time whether these changes are reversible,but at least one study suggests that denervation can bereversed after surgery.25

On a molecular level, denervation of skeletal muscleleads to increased expression of NF-kB, FOXO1, andatrogin-1 and subsequent increased muscle atrophy.35

Dreyer et al29 have shown that denervation through spinalcord injury results in a reduction in phosphorylation ofmTOR, S6K1, and eIF4G. They conclude that paraplegia-induced muscle atrophy in rats is associated with generaldownregulation of the mTOR signaling pathway. Similarly,Agata et al1 found decreased expression of mTOR and Aktin denervated soleus muscles, a change that could bealtered with mechanical stretch. These studies suggest thatdenervation influences several of the same pathways thathave been found to alter regulation with muscle atrophy.The combination of mechanical unloading and denervationmay significantly influence the development of the degen-erative changes seen after RCTs.

Conclusions/future directions

Despite the important clinical consequences of muscleatrophy and fatty infiltration in the outcomes of rotatorcuff repair, little is understood about the underlyingpathophysiology involved in these characteristic physicalchanges. Future studies should focus on understanding thecellular and molecular regulation of muscle atrophy,fibrosis, and fatty infiltration to develop novel pharma-cologic and surgical treatment modalities to improve theclinical outcomes in the setting of massive RCTs. Withthis understanding, cell-based therapies could play animportant role in treating muscle atrophy. Although themajority of basic science rotator cuff studies have focusedon the tendon and improving tendon-to-bone healing, thenext step in improving clinical outcomes will come fromunderstanding and altering the changes seen within thecuff muscles after RCTs.

Acknowledgments

We thank the University of California, San Franciscoand the San Francisco VA Medical Center for theirfinancial support and use of equipment.

Disclaimer

The authors, their immediate families, and any researchfoundations with which they are affiliated have not

172 D. Laron et al.

received any financial payments or other benefits fromany commercial entity related to the subject of thisarticle.

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