Download Do Mouse Arm Muscles Serve as a Good Model of Human Arm

Do Mouse Arm Muscles Serve as a Good Model of Human Arm Muscles?
1
Mathewson, M A; 1Chapman, M A; +1,2Lieber, R L
University of California San Diego, Dept. of Bioengineering, San Diego, CA, 2University of California San Diego, Dept. of Orthopedics, San Diego, CA
[email protected]
RESULTS:
Increasing excursion
FDP
FDP
mouse
PCSA (normalized to FCR)
3.5
human
FDS
3.0
Brach
2.5
FDS
PT
2.0
Bic S
Brach
Bic L
FCU
1.5
PT
1.0
PQ
Tri Lat
ECRB
EDC
ECU
ECRL
FCR FCR
ECRB
PL
ECRL
Brach
EDC
PL
EIP
EDQuint
EIP
EDQuint
Bic L
ECU
0.5
PQ
0.0
0.0
0.5
Increasing force
4.0
1.0
Bic S
Tri Lat
1.5
Tri Long
2.0
2.5
3.0
Lfn (normalized to FCR)
Figure 1: Normalized PCSA vs. fiber length. Higher PCSA suggests
greater force production, and longer fibers, greater speed. Tri Long had a
normalized PCSA more than fourfold larger than all other muscles and
was excluded for easier visualization.
The mouse forearm (excluding the paw) shows structural similarities
to that of the human. However, the upper arm has noticeably different
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Architectural Difference Index
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Wrist flexor/extensor
Digital flexor/extensor
Pronator
Upper arm
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PT
Br
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Bi
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Bi
cS
Tr
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g
Tr
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at
PQ
FD
S
P
EI
FD
P
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Q
ui
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ED
PL
ED
FC
U
FC
R
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METHODS:
All procedures were performed with approval of the University of
California Institutional Animal Care and Use Committee. Six adult male
C57BL/6 mice (Mus musculus) were euthanized and the forelimbs
removed. One limb per mouse was pinned with the elbow at 90° for
fixation in 10% buffered Formalin. Under a dissection microscope, these
fixed muscles were carefully dissected out. Twenty-two distinct muscles
were found, three of which had separate heads, giving a total of 27
individually dissected muscles: Abductor Pollicis Longus (APL),
Anconeus (Ancon), Biceps Brachii Long (Bic L) and Short (Bic S) head,
Brachialis (Brach), Coracobrachialis (Coraco), Dorso-Epitrochliear
Brachii (DEB), Extensor Carpi Radialis Brevis (ECRB) and Longus
(ECRL), Extensor Carpi Ulnaris (ECU), Extensor Digiti Quarti
(EDQuart) and Quinti (EDQuint), Extensor Digitorum Communis
(EDC) and Lateralis (EDL), Extensor Indicis Proprius (EIP), Flexor
Carpi Radialis (FCR), Flexor Carpi Ulnaris (FCU), Flexor Digitorum
Profundus Radial (FDP R), Superficial (FDP S), and Ulnar (FDP U)
head, Flexor Digitorum Superficialis (FDS), Palmaris Longus (PL),
Pronator Quadratus (PQ), Pronator Teres (PT), Triceps Brachii Lateral
(Tri Lat), Long (Tri Long), and Medial head (Tri Med).
Muscle mass, muscle length (Lm), fiber length (Lf), pennation angle,
and sarcomere lengths (Ls) were measured as previously described
(Lieber et al., 1994). Normalized fiber (Lfn) and muscle (Lmn) lengths
were calculated by normalizing to a Ls of 2.4 µm. Physiological cross
sectional area (PCSA) was calculated from architectural variables
(Lieber et al. 1990). Previously published human forearm data were
used for comparison (Lieber et al. 1992a).
To compare muscle properties more accurately between species, the
architectural difference index (ADI) was calculated. (Lieber et al.
1992b) This number combines calculated differences between five
selected architectural variables (Lfn, Lmn, mass, PCSA, and Lfn:Lmn ratio)
to create a single number, which allows normalization of muscles so that
they can be compared across groups and species.
proportions, with a much larger contribution from the triceps. There are
several other fundamental differences in musculature between mouse
and human. The mouse arm has an EDL, EDQuart, and DEB, all of
which are absent in the human. In addition, the mouse is missing a
brachioradialis muscle and has neither thumb flexors nor thumb
extensors.
PCSA and fiber length were normalized to the FCR (which shows
architectural and functional similarity between species) and plotted
(Figure 1) to enable graphical comparison between species. Muscles
with greater relative PCSAs are designed for force production, and those
with longer fiber lengths for greater excursion. The ADI (Figure 2)
showed more than a five-fold difference between the most and least
similar muscles of the two species. High similarity, (defined in this study
as an ADI < 0.5) was seen in the ECRL, FCR, PL, EDC, EIP, PQ, and
PT. An ADI > 2, as seen in the muscles of the triceps, indicates a large
difference between muscles. All muscles of the forearm besides the
digital flexors had an ADI < 1, suggesting similarity to humans.
ADI
INTRODUCTION:
Given the explosion in the use of mouse models to study human
disease, it is critical to define the extent (if any) to which mouse muscle
anatomy accurately represents human muscle anatomy. While mouse
models have spurred significant breakthroughs, examples exist of studies
performed in mice that were ultimately not replicable in humans. To
insure that mouse forelimb anatomy is appropriately applied to human
muscle disorders, the purpose of our study was to characterize the
architectural design of muscles and muscle fibers in the mouse arm.
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1
Figure 2: Architectural difference index (ADI) of select human and
mouse muscles shows relative similarity between pairs of muscles based
on architectural parameters. Lower ADI indicates greater similarity
DISCUSSION:
This study demonstrates that mouse and human arm muscles are, in
many cases, similar, as seen by comparing architectural design (Figure
1) and ADI values (Figure 2). For example, pronators, digital extensors,
and select wrist muscles show high overall architectural similarity to
their human counterparts. However, digital flexors and all muscles of the
upper arm show little similarity to those of humans. Obviously, some
muscles of great interest in human disorders, such as the brachioradialis,
cannot be studied at all in mice since they are absent. Based on these
composite architectural data, it appears that, with careful consideration,
mice may provide a reasonable experimental estimate of the forearm.
The upper arm, likely because of differences in usage patterns due to
quadrapedal rather than bipedal locomotion, shows a high degree of
difference from that of the human. This suggests that studies of upper
arm dysfunction could be better modeled in a different animal. Overall,
care should be taken when choosing acceptable mouse muscles for
studies of corresponding human disease.
SIGNIFICANCE:
Due to their size, cost, and availability, mice are frequently used in
studies as models of human disease. By thoroughly characterizing the
arm of this traditional model, we were able to shed light on the extent to
which specific mouse muscles accurately represent humans.
REFERENCES:
Lieber et al. (1990). J. Hand Surg. 15A, 244- 250.
Lieber et al. (1992a). J. Hand Surg. 17, 787-798.
Lieber et al. (1992b). J. Biomech. 25, 557-560.
Lieber et al. (1994). J. Neurphysiol. 71, 874- 888.
Poster No. 2276 • ORS 2012 Annual Meeting