J Shoulder Elbow Surg (2015) 24, 111-119
www.elsevier.com/locate/ymse
BASIC SCIENCE
Reduced muscle fiber force production
and disrupted myofibril architecture
in patients with chronic rotator cuff tears
Christopher L. Mendias, PhD, ATCa,b,*, Stuart M. Roche, BS, CSCSa,
Julie A. Harning, BSa, Max E. Davis, BAa, Evan B. Lynch, MSa,b,
Elizabeth R. Sibilsky Enselman, MEd, ATCa, Jon A. Jacobson, MDc,
Dennis R. Claflin, PhDd,e, Sarah Calve, PhDf, Asheesh Bedi, MDa
a
Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
c
Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA
d
Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, USA
e
Department of Surgery, Section of Plastic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
f
School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
b
Background: A persistent atrophy of muscle fibers and an accumulation of fat, collectively referred to as
fatty degeneration, commonly occur in patients with chronic rotator cuff tears. The etiology of fatty degeneration and function of the residual rotator cuff musculature have not been well characterized in humans.
We hypothesized that muscles from patients with chronic rotator cuff tears have reduced muscle fiber force
production, disordered myofibrils, and an accumulation of fat vacuoles.
Methods: The contractility of muscle fibers from biopsy specimens of supraspinatus muscles of 13
patients with chronic full-thickness posterosuperior rotator cuff tears was measured and compared with
data from healthy vastus lateralis muscle fibers. Correlations between muscle fiber contractility, American
Shoulder and Elbow Surgeons (ASES) scores, and tear size were analyzed. Histology and electron microscopy were also performed.
Results: Torn supraspinatus muscles had a 30% reduction in maximum isometric force production and a
29% reduction in normalized force compared with controls. Normalized supraspinatus fiber force positively correlated with ASES score and negatively correlated with tear size. Disordered sarcomeres were
noted, along with an accumulation of lipid-laden macrophages in the extracellular matrix surrounding
supraspinatus muscle fibers.
Conclusions: Patients with chronic supraspinatus tears have significant reductions in muscle fiber force
production. Force production also correlates with ASES scores and tear size. The structural and functional
muscle dysfunction of the residual muscle fibers is independent of the additional area taken up by fibrotic
This work was funded by a research grant from the American Shoulder and
Elbow Surgeons.
This study was approved by the University of Michigan Medical School
IRB (approval # HUM00037757).
This paper is the 2014 Basic Science Neer Award winner.
*Reprint requests: Christopher L. Mendias, PhD, ATC, Department of
Orthopaedic Surgery, University of Michigan Medical School, 109 Zina
Pitcher Place, BSRB 2017, Ann Arbor, MI 48109-2200, USA.
E-mail address: [email protected] (C.L. Mendias).
1058-2746/$ - see front matter Ó 2015 Journal of Shoulder and Elbow Surgery Board of Trustees.
http://dx.doi.org/10.1016/j.jse.2014.06.037
112
C.L. Mendias et al.
tissue. This work may help establish future therapies to restore muscle function after the repair of chronically torn rotator cuff muscles.
Level of evidence: Basic Science, Histology.
Ó 2015 Journal of Shoulder and Elbow Surgery Board of Trustees.
Keywords: Rotator cuff; fatty degeneration; myosteatosis; permeabilized muscle fibers; macrophages;
sarcomeres
Rotator cuff tears are among the most debilitating and
frequent upper extremity injuries, with more than 250,000
surgical repairs performed annually in the United States.7
Although there have been important improvements in surgical repair and rehabilitation techniques, many patients
continue to have symptoms after repair, and re-tear rates for
surgical repair of full-thickness tears remain high.2,11 A set
of common pathologic changes often occurs in patients
with chronically torn rotator cuff muscles, including muscle
fiber atrophy, fibrosis, and accumulation of fat within and
around muscle fibers.15 These changes are commonly
referred to as fatty degeneration. The severity of fatty
degeneration is positively correlated with poor functional
outcomes, and despite successful surgical repair of the tear
of the torn rotator cuff, fatty degeneration often does not
improve after repair and for some patients continues to
worsen over time.13,14
Given the anatomic and biomechanical complexity of the
shoulder girdle, it can be challenging to specifically isolate the
rotator cuff during strength testing in the clinical setting,24
making it difficult to measure rotator cuff function by conventional biomechanical testing methods. Whole muscle
force measurements have been performed in rotator cuff
muscles from sheep and rats,20,22 but these techniques are
invasive and can be difficult to perform in a fashion that allows
the animal to recover. Whereas whole muscle force measurements can be informative, force measurements from
single muscle fibers obtained from small tissue biopsy specimens provide a wealth of information about the function of
muscle as a whole and are predictive of strength measurements performed at the whole muscle level.6,19 Using a rat
model of full-thickness rotator cuff tears, we measured force
production of individual muscle fibers and demonstrated a
40% reduction in maximum isometric force (Fo) and an 18%
reduction in specific force (sFo, defined as Fo normalized to
the muscle fiber cross-sectional area [CSA]) in torn muscles
compared with controls.16 This reduction in Fo and sFo at the
level of individual muscle cells indicates that chronic rotator
cuff tears disrupted the abundance or function of myofibrils,
which are the fundamental contractile structures of muscle
cells. Further, whereas fat accumulation was previously noted
to occur in animal models of chronic rotator cuff tears, we
identified a pool of macrophages that accumulate around fatty
plaques present in injured rotator cuff muscles.16 Although
these studies provided insight into potential mechanisms that
result in muscle weakness after rotator cuff tears, the pathophysiologic mechanism of fatty infiltration and the impact of
chronic tears on the ability of the rotator cuff muscle fibers to
generate force in humans have not been defined.
The primary objective of this study was to measure the
contractile and morphologic properties of muscle fibers
from patients with chronic rotator cuff tears. A secondary
objective was to determine if there were correlations between muscle fiber contractility and American Shoulder
and Elbow Surgeons (ASES) survey instrument scores or
the size of the tear. We hypothesized that patients with
rotator cuff tears would have reduced muscle fiber force
production compared with healthy muscle fibers and that
force production would be positively correlated with ASES
scores and negatively correlated with tear size.
Materials and methods
Subjects
All subjects provided informed, written consent before participation in this study. Subjects who were 18 years of age or older, who
had a full-thickness supraspinatus tear as diagnosed by ultrasound
or magnetic resonance imaging, had a history of shoulder pain for
at least 5 years, and consented to undergo arthroscopic rotator cuff
examination were eligible for participation in the study. Patients
who were undergoing revision rotator cuff tear, had previous
shoulder or upper extremity surgery, or had a history of a myopathy or metabolic or rheumatologic disorder were excluded from
participation in the study. Patients also completed the ASES survey instrument to measure shoulder-specific function26 1 week
before surgery. The ASES activities of daily living (ADL) subscale for the involved shoulder as well as the composite score that
includes the ADL of the uninvolved shoulder and a visual analog
pain scale were used for analysis.
Diagnostic imaging
The diagnosis of a full-thickness supraspinatus tear was assessed
from ultrasound or magnetic resonance imaging studies before
surgery. The gap distance between the free tendon end and the
anatomic footprint on the humeral head was measured from scans
in coronal and sagittal planes. A single board-certified and
fellowship-trained musculoskeletal radiologist read the imaging
studies and calculated the gap distances with Imagecast PACS 3.6
software (IDX Systems, Burlington, VT, USA).
Rotator cuff tears and muscle contractility
Surgical repair and muscle biopsy
113
A single board-certified and fellowship-trained orthopedic surgeon
performed surgical repairs and muscle biopsies. All patients had a
posterosuperior rotator cuff tear, and the torn supraspinatus tendon
was fully mobilized and repaired to the anatomic footprint by a
transosseous-equivalent, double-row technique. After repair,
biopsy specimens were taken from the distal quarter of the
supraspinatus with an arthroscopic duckbill basket punch instrument (Arthrex, Naples, FL, USA). The biopsied tissue was
immediately trimmed, prepared, and processed for muscle fiber
contractility measurements or imaging studies.
USA) as well as BODIPY FL to identify lipid (Invitrogen, Grand
Island, NY, USA), DAPI (Sigma-Aldrich, St Louis, MO, USA) to
identify nuclei, and wheat germ agglutinin conjugated to Alexa
Fluor 555 (WGA-AF555; Invitrogen) to identify extracellular
matrix. Streptavidin conjugated to Alexa Fluor 647 (Invitrogen)
was used to detect CD68 antibodies. Sections were visualized with
an Axioplan 2 microscope (Zeiss, Thornwood, NY, USA) equipped with AxioCam cameras (Zeiss). Sections were taken with use
of the 10 objective to visualize lipid and extracellular matrix,
and as the macrophage signal is appreciable only under highpower magnification, the 40 objective was used to identify
macrophages, extracellular matrix, and lipid signal.
Muscle fiber contractility
Transmission electron microscopy
The contractility of muscle fibers was measured by previously
described techniques and solutions.6,16,17,21 Briefly, bundles of
muscle fibers approximately 5 mm in length and 0.5 mm in
diameter were dissected from supraspinatus muscle biopsy specimens and exposed to skinning solution for 30 minutes. Bundles
were then transferred to storage solution for 16 hours at 4 C and
then stored at 80 C until use. On the day of an experiment,
bundles of muscle fibers were thawed on ice, and single fibers were
pulled from bundles with fine mirror-finished forceps. Fibers were
then placed in a chamber containing relaxing solution and secured
at one end to a force transducer (Model 403A; Aurora Scientific,
Aurora, ON, USA) and at the other end to a servomotor (Model
322C; Aurora Scientific). Two ties of 10-0 monofilament nylon
suture were used to secure each end of the fiber to the force
transducer and servomotor. With a laser diffraction measurement
system, the length of the fiber (Lf) was adjusted to obtain a
sarcomere length of 2.7 mm, which is the optimum length for
human fibers based on the thin filament length measurements of
Walker.31 The average CSA of the fiber was calculated assuming an
elliptical fiber cross section, with diameters obtained at 5 different
positions along the fiber from high-magnification images of the top
and the side views. Maximum isometric force (Fo) of the fiber was
elicited by immersing the fiber in a high calcium-containing activation solution. Specific force (sFo) was calculated by dividing Fo
by CSA. Up to 20 fast fibers were tested from each subject with a
supraspinatus tear, and those fibers that did not demonstrate tearing
or slipping were used for analysis. The average value from each
subject was used in statistical analyses. Single-fiber contractility
measurements in the current study were compared with the values
obtained from healthy vastus lateralis biopsy specimens from the
65- to 80-year-old pooled male and female pre-training cohorts
(N ¼ 27 subjects) that were previously reported.6
Biopsied tissue used for electron microscopy was rinsed free of
blood with saline and fixed immediately with 2.5% glutaraldehyde
solution in 0.1 M Sorensen buffer (Electron Microscopy Sciences,
Hatfield, PA, USA). Tissue was then post-fixed with 1% osmium
tetroxide in 0.1 M Sorensen buffer (Electron Microscopy Sciences), dehydrated through a graded ethanol series, and then
embedded in an epoxy resin (Sigma-Aldrich). One-micron sections were cut on an ultramicrotome and stained with 1% toluidine
blue for evaluation by light microscopy. Ultrathin sections were
obtained by cutting specimens longitudinally with a diamond
knife ultramicrotome and post-staining with uranyl acetate and
lead citrate. Sections were visualized with a CM-100 transmission
electron microscope equipped with a high-resolution digital
camera (Philips, Mahwah, NJ, USA).
Histology
Histology was performed as previously described.16,17 Biopsied
tissue was rinsed free of blood with saline and was snap frozen in
Tissue-Tek (Sakura, Torrance, CA, USA) with isopentane cooled
in liquid nitrogen and stored at 80 C until use. Muscles were
sectioned at a thickness of 10 mm and prepared for immunohistochemistry. To identify lipid deposition and macrophages, sections were fixed in 4% paraformaldehyde, permeabilized in 0.1%
Triton X-100 in phosphate-buffered saline, blocked in 5% goat
serum, and incubated with biotinylated antibodies against the
macrophage-specific antigen CD68 (AbCam, Cambridge, MA,
Statistics
Values in the text are presented as mean standard deviation.
Tukey box plots are used to present data in Figure 1. Differences
between size and contractility values of torn supraspinatus muscles in the current study were compared with values from the
vastus lateralis muscles of healthy control 60- to 85-year-old
subjects by t tests (a ¼ .05). Linear regression analysis was also
used to determine the correlation between muscle fiber contractility and other measured parameters. Prism 6.0 software
(GraphPad Software, La Jolla, CA, USA) was used to conduct
statistical analyses.
Results
The age of patients in this study was 53 7 years (range,
45-70 years), with 8 men and 5 women. Patients had an
ASES ADL score of 13 4.8 (range, 5-19 of a possible 30)
for the involved shoulder and a composite ASES score of
46 18 (range, 13-75 of a possible 100). The biopsy
specimens of supraspinatus muscles of patients in this study
showed the typical fat accumulation as has been described
previously (Fig. 1, A), with the presence of canonical adipocytes as well as numerous large lipid droplets present in
and around muscle fibers. By transmission electron microscopy, highly disordered sarcomeres with a loss of
uniform force-transmitting Z discs and abnormally shaped
114
C.L. Mendias et al.
Figure 1 Representative histology and electron microscopy of torn supraspinatus muscles. (A) A 10 magnification view demonstrating
canonical adipocytes (asterisk) and large lipid droplets in and around muscle fibers (yellow arrowheads). White, extracellular matrix (ECM;
WGA Lectin-AF555); green, lipid (BODIPY); blue, nuclei (DAPI). (B and C) Two different 40 magnification views demonstrating lipidladen macrophages in the muscle extracellular matrix. White, extracellular matrix (ECM; WGA Lectin-AF555); green, lipid (BODIPY);
red, macrophage (CD68); blue, nuclei (DAPI). (D) Transmission electron micrograph demonstrating disordered, unaligned sarcomeres with
a loss of uniform Z discs (arrowhead) and large, abnormally shaped mitochondria surrounding lipid droplets (asterisks). (E) Infiltration of
collagen fibrils (arrowheads) and large vesicles (asterisk) containing lipid droplets, mitochondria, and myofibrillar proteins. (F) Multinuclear syncytium of macrophages containing numerous lipid droplets in the muscle extracellular matrix.
mitochondria were also present throughout multiple biopsy
specimens (Fig. 1, D). Areas of fibrosis and large vesicles
containing lipids, mitochondria, and sarcomeric proteins
were also observed (Fig. 1, E). An accumulation of multinuclear complexes of macrophages (Fig. 1, B, C, and F)
was also frequently noted.
We next determined if the structural changes observed
by histology and electron microscopy would affect muscle
fiber force production. As most of the patients seeking rotator cuff repair had a long history of reduced shoulder
function and atrophy, and many had bilateral symptoms, it
was not possible to use another shoulder girdle muscle or
the contralateral side as a control. We therefore compared
the contractile and morphologic values of fibers from the
current study with a previously published study from our
laboratory6 that measured similar parameters from vastus
lateralis fibers from otherwise healthy 60- to 85-year-old
male and female subjects. As shown in Figure 2, CSA of
the fibers from the healthy controls in the previous study
(VL, Fig. 2, A; P ¼ .871) was similar to that of the fibers
from patients with supraspinatus tears in the current study
(SSP), but there was a 30% reduction in maximum isometric force (Fo, Fig. 2, B; P < .002) and a 29% reduction
in specific force (sFo, Fig. 2, C; P < .001) in patients with
chronic supraspinatus tears. A video demonstrating force
measurement from a healthy vastus lateralis muscle fiber
and from a chronically torn supraspinatus muscle is shown
in Supplemental Video 1.
Finally, we evaluated whether different clinical parameters correlate with supraspinatus muscle fiber morphology
and contractility. ASES ADL scores did not correlate with
tear size, but ASES total score did negatively correlate with
tear size (Fig. 3, A and B). The size of the tear did not
correlate with muscle fiber CSA or Fo (Fig. 4, A and B), but
a negative correlation was observed between tear size and
sFo (Fig. 4, C). No correlations were observed between
ASES ADL scores of the affected shoulder and fiber CSA
or Fo (Fig. 5, A and B), but a positive correlation was
observed between ASES ADL scores of the affected
shoulder and sFo (Fig. 5, C). Similar results were observed
for the composite ASES scores (Fig. 5, D-F). We also did
not observe significant correlations between age and ASES
Rotator cuff tears and muscle contractility
115
Figure 2 Contractile properties of permeabilized type II muscle fibers from healthy, control vastus lateralis muscles (VL) and torn
supraspinatus muscles (SSP). (A) Cross-sectional area, (B) maximum isometric force (Fo), and (C) specific force (sFo, Fo normalized to
cross-sectional area) of fibers. Values are presented as Tukey box plots, and differences between groups were tested by t tests (a ¼ .05).
*Different from SSP group. N ¼ 27 subjects for VL; N ¼ 13 subjects for SSP. Values for VL data set are from Claflin et al.6
Figure 3 Correlations between ASES scores and the size of the gap between the free tendon end and the anatomic attachment of torn
supraspinatus (SSP) muscles. (A) ASES affected shoulder ADL score and (B) ASES composite score as a function of SSP tear gap size.
ADL score (R2 < 0.01; P ¼ .92), ASES total score
(R2 ¼ .02; P ¼ .66), CSA (R2 ¼ 0.02; P ¼ .68), Fo
(R2 ¼ 0.04; P ¼ .45) and sFo (R2 ¼ 0.03; P ¼ .55). As no
differences with regard to age were observed, these data are
not presented in graphical format.
Discussion
Understanding the pathophysiologic changes that occur in
the muscles of patients with chronic rotator cuff tears is of
critical importance to improving outcomes for these patients. This was the first study, to our knowledge, that
measured the contractility and characterized the ultrastructure of muscles at the single-cell level from patients
with chronic rotator cuff tears and correlated these changes
to outcomes scores and imaging studies. We identified a
striking deficit in specific force production of the residual
muscle fibers and also observed structural abnormalities in
the architecture of muscle contractile proteins and abnormalities in the shape of mitochondria surrounding lipid
droplets. Further, we have identified a population of lipidladen macrophages present in the extracellular matrix of
patients with torn rotator cuff muscles that may offer
insights into the pathophysiologic process and therapeutic
modulation of fatty infiltration of the rotator cuff musculature in patients with chronic tears.16,17 Finally, normalized force production was observed to have a negative
correlation with tear size and a positive correlation with
ASES scores. Combined, these results identify chronic
structural and mechanical changes in torn rotator cuff
muscles that may explain the poor functional capacity of
the muscles after repair and provide biologic support for the
utility of ASES scores and gap size in predicting muscle
function in patients with rotator cuff tears.
Myofibrils, which are composed of repeating segments
of sarcomeres, are the fundamental organelles within
muscle fibers that generate force. The forces generated
within sarcomeres are transmitted laterally to the extracellular matrix surrounding muscle fibers by Z discs.25 An
increase in the number of myofibrils in parallel will
increase the total force production of muscle, whereas a
decrease will lead to reduced total muscle force production.28 Exercise or inactivity can change the size and total
force-generating capacity of muscle fibers, but the change
in the number of myofibrils in healthy muscles is proportional to the change in size of the fiber.6,29,30 The ratio of
muscle fiber CSA to maximum isometric force production
(Fo) is specific force (sFo), and decreases in sFo typically
suggest a deficit in the production of healthy, properly
aligned sarcomeres. sFo is therefore an important functional
biomarker of the health of a muscle fiber, and decreases in
sFo can indicate bonafide pathologic changes in the muscle
tissue.8,16,21 In addition, whereas CSA and Fo can change
between different muscles in the body, sFo is a parameter
that is thought to be consistent across healthy fibers
116
C.L. Mendias et al.
Figure 4 Correlations between single-fiber contractility parameters and the size of the gap between the free tendon end and the anatomic
attachment of torn supraspinatus (SSP) muscles. (A) Cross-sectional area (CSA), (B) maximum isometric force (Fo), and (C) specific force
(sFo, Fo normalized to cross-sectional area) of fibers as a function of SSP tear gap size.
Figure 5 Correlations between ASES scores and single-fiber contractility parameters of torn supraspinatus (SSP) muscles. ASES affected
shoulder ADL score as a function of (A) cross-sectional area, (B) maximum isometric force (Fo), and (C) specific force (sFo, Fo normalized
to cross-sectional area) of torn SSP fibers. ASES composite score as a function of (D) cross-sectional area, (E) maximum isometric force
(Fo), and (F) specific force (sFo, Fo normalized to cross-sectional area) of torn SSP fibers.
containing the same myosin isoforms from different muscles in the body and is not anticipated to change on the
basis of the anatomic location of the muscles.4 Previous
studies have identified no differences in sFo between fibers
from upper and lower extremity muscles in humans10,23 or
any aging-associated changes in healthy rotator cuff muscles in adult and old rats.16,17 The sFo of type II fibers from
lower extremity muscles are therefore expected to be
similar to the sFo values of type II fibers from muscles of
the upper extremity.
In the current study, we tested the contractility of permeabilized fibers from patients with chronic supraspinatus
(SSP) tears and compared these values with those obtained
from the uninjured, untrained vastus lateralis (VL) muscles
of healthy 65- to 80-year-old men and women.6 Whereas
the size of the fibers was similar between the control VL
and injured SSP muscles, SSP muscles had a reduction in
Fo and a subsequent decrease in sFo. These findings are
consistent with reductions in sFo that were observed in rat
models of rotator cuff tears.16,17 There was malalignment in
the orientation of Z discs, which likely disrupts the proper
transmission of force generated in the myofilaments to the
cytoskeleton of the fiber. Although there was an accumulation of lipid and fibrotic extracellular matrix, as optimal
force production requires precise alignment of the contractile proteins, we speculate that the sarcomeric disorder
observed in the electron micrographs contributed to the
reduction in sFo observed in the fibers from injured SSP
muscles. There was also a negative correlation between sFo
and objective and subjective clinical measurements. sFo
was negatively correlated with the gap size of the tendon
tear, and this is consistent with the clinical finding that
patients with greater gap sizes tend to have worse clinical
outcomes.2,14 sFo was also positively correlated with subjective, patient-completed ASES surveys, suggesting that
there is a connection between patient-perceived shoulder
Rotator cuff tears and muscle contractility
function and the ability of SSP muscles to generate force.
The reduction in sFo in the current study is consistent with
the findings of Gerber et al,13 who identified a negative
correlation between whole muscle force production and
force normalized to anatomic CSA in patients undergoing
rotator cuff repair. However, Gerber postulated that the
reduction in normalized force production was due to fat and
connective tissue taking up area in muscle cross sections.
Whereas our results are in general agreement, the findings
of the current study suggest that the decrease in sFo occurs
at the level of the muscle fiber independent of the additional
area taken up by fibrotic tissue and fat in a muscle cross
section. In addition, although the prevalence of rotator cuff
tears increases with age,32 we did not observe correlations
between age and muscle fiber contractility, ASES scores, or
tear size. Overall, our results indicate that patients with
chronic rotator cuff tears have highly disordered sarcomeres that prevent proper force generation and that parameters used for clinical decision making, such as gap size
and patient-perceived function, correlate well with rotator
cuff sFo values.
The ultrastructure of the rotator cuff musculature in patients with chronic rotator cuff tears as reported in the
current study is of paramount importance to understanding
of the pathophysiologic mechanism of fatty infiltration and
atrophy. The deposition of fat in and around muscle fibers is
commonly observed after chronic rotator cuff tear.15,27 The
ontogeny of fat accumulation and the specific cells and
signaling pathways that drive this process in rotator cuff
tears remain largely unknown. Atherosclerosis is a wellstudied condition that is marked by an accumulation of
lipid and local tissue inflammation5 and shares some similar
features with chronic rotator cuff tears. In atherosclerosis, a
population of fatty macrophages, often referred to as foam
cells, take up high levels of lipid and promote local tissue
inflammation.5 We previously identified a population of
lipid-laden macrophages in rat models of chronic rotator
cuff tears.16,17 In the current study, we also report the
presence of lipid-laden macrophages, as identified by the
presence of lipid droplets and staining for the panmacrophage marker CD68.3 These lipid-laden macrophages in torn SSP muscles also share similar morphologic
features with foam cells visualized with transmission electron microscopy.1,18 As foam cells promote local tissue
inflammation in blood vessels, current interventions that
prevent or decrease foam cell accumulation are being
studied as potential therapeutic modalities in the treatment
of atherosclerosis.9 Although it is not known whether the
lipid-laden macrophages present in torn rotator cuff muscles
play a role in tissue inflammation or muscle function, given
the important role that these cells have in atherosclerosis,
this is an area of research that deserves further study.
This paper has several limitations. We did not have
access to healthy, age-matched control SSP muscles, as this
would require performing arthroscopic biopsies of a large
cohort of subjects, and instead used the VL as a control
117
muscle. The results are also biased toward patients with
rotator cuff tears who chose to undergo surgery. Whereas
the sFo production of healthy VL and SSP muscles is
anticipated to be similar, it is possible that the sFo for
healthy SSP muscles is different from that of VL muscles.
Although we correlated muscle fiber contractility by tear
size and ASES scores, we could not perform correlations
based on Goutallier score. Not all patients had magnetic
resonance imaging scans; some had only ultrasound performed to verify the clinical diagnosis of a rotator cuff tear
and did not have reliable images to characterize the severity
of fatty infiltration. As many patients with chronic, fullthickness tears do not know the specific time when their
injury occurred, we do not know whether the time since
suffering a tear has an impact on SSP muscle contractility.
We also took biopsy specimens at the time of surgical
repair, but we did not perform repeated biopsies to determine if repair is able to improve the contractile properties
of torn SSP muscles. These limitations notwithstanding, the
study provided important insight into the cellular and
molecular pathophysiology of chronically torn rotator cuff
muscles and provided biologic corroboration for commonly
used clinical assessment parameters and tools that are used
to predict rotator cuff function.
Despite improvements in surgical repair and rehabilitation techniques, rotator cuff tears remain among the most
debilitating and frequent upper extremity injuries.2,7 Current treatment options are limited and are mostly aimed at
addressing symptoms and not treating the underlying
pathologic process.2 For many patients who undergo successful repair of their chronically torn rotator cuff, fatty
degeneration continues to progress over time.13,14 The
repair of chronically torn rotator cuff muscles subjects the
chronically shortened muscle to a substantial and rapid
length change that may be injurious to the muscle. Given
the changes in myofibril architecture observed in the current study, inducing such a rapid length change at the time
of surgical repair likely generates a second injury that can
be difficult for the muscle to recover from. Using a sheep
model, Gerber et al12 demonstrated that a slow, progressive
lengthening of chronically torn rotator cuff muscles could
reduce fatty degeneration and restore normal muscle
architecture. This approach probably allows the muscle to
slowly remodel and to adapt to new tension being placed
on it. Therapeutic interventions that target sarcomere
and membrane stability may therefore be beneficial in
enhancing the regeneration of chronically torn rotator cuff
muscles and improve overall patient outcomes.
Conclusions
Patients with chronic rotator cuff tears often have a
persistent atrophy of muscle fibers and an accumulation
of fatty and fibrotic tissue, collectively referred to as
118
fatty degeneration. Although several animal studies have
provided insight into potential mechanisms that result in
muscle weakness after rotator cuff tears, the pathophysiologic mechanism of fatty infiltration and the
impact of chronic tears on the ability of the rotator cuff
muscle fibers to generate force in humans had not been
defined. The current study demonstrated that patients
with chronic rotator cuff tears have significant reductions in muscle fiber force production, disrupted
myofibril architecture, and accumulation of fatty macrophages in the muscle extracellular matrix. We also
observed that normalized force production had a negative correlation with tear size and a positive correlation
with ASES scores. This work helps explain the cellular
and molecular basis for the reduced upper extremity
function of patients with chronic tears, provided additional biologic validation for the use of ASES scores and
tear size measurements in predicting shoulder function,
and will, it is hoped, contribute to the development of
future therapies to improve functional outcomes and
enhance rotator cuff regeneration.
Disclaimer
The authors, their immediate families, and any research
foundation with which they are affiliated have not
received any financial payments or other benefits from
any commercial entity related to the subject of this article.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.jse.2014.06.037.
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