Muscle Biochemistry
Eric C. Niederhoffer, Ph.D.
Associate Professor, Biochemistry & Molecular Biology
Copyright 2001-2004, E.C. Niederhoffer. All Rights Reserved.
All trademarks and copyrights are the property of their respective owners.
Overview
Resources (Where to go for more)
Muscle organization (What it looks like)
Muscle proteins (Who's involved)
Metabolic pathways (What powers muscle)
Role of calcium (What a small signal)
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Resources
Neuromuscular Home Page (Washington University)
Muscle contraction (animated GIF, QuickTime1, QuickTime2)
Brown, R. H., Jr. 1997. Dystrophin-associated proteins and the muscular dystrophies.
Annual Review of Medicine 48:457-466.
Carlson, C. G. 1998. The dystrophinopathies: an alternative to the structural hypothesis.
Neurobiology of Disease 5:3-15.
Devlin, T. M. (ed.). 1997. Textbook of biochemistry with clinical correlations, 4th ed.
John Wiley & Sons, Inc., New York.
Geeves, M.A., and K. C. Holmes. 1999. Structural mechanism of muscle contraction.
Annual Review of Biochemistry 68:687-728.
Mendell, J.R., R. C. Griggs, and L. J. Ptácek. 1998. Diseases of muscle, pp. 24732483. In A. S. Fauci, E. Braunwald, K. J. Isselnacher, J. D. Wilson, J. B. Martin, D. L.
Kasper, S. L. Hauser, and D. L. Longo (ed.), Harrison's principles of internal medicine,
14th ed. McGraw-Hill, Inc., New York.
Worton, R. G., M. J. Molnar, B. Brais, and G. Karpati. 2001. The muscular
dystrophies, p. 5493-5523. In C. R. Scriver, A. L. Beaudet, W. S. Sly, D. Valle, B.
Childs, K. W. Kinzler, & B. Vogelstein (ed.), The metabolic and molecular bases of
inherited disease, 8th ed. McGraw-Hill, Inc., New York.
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Muscle Organization
Tissue
bone, muscle, tendon, and nerve
muscle fiber, myofibril
Filaments
sarcomere
sarcomere (micrograph)
thick and thin filaments (micrograph)
Muscle Organization
(http://www.life.uiuc.edu/crofts/bioph354/images/muscle1.jpg)
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Muscle Organization
(http://www.life.uiuc.edu/crofts/bioph354/images/myofib2.jpg)
Muscle Organization
(http://www.life.uiuc.edu/crofts/bioph354/images/sarcom2.jpg)
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Muscle Organization
(http://www.life.uiuc.edu/crofts/bioph354/images/sarcomere.jpg)
Muscle Organization
(http://www.life.uiuc.edu/crofts/bioph354/images/sciemyosin3.jpg)
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Muscle Proteins
Table of muscle proteins
Table of muscle proteins correlated to diseases
Actin-myosin complex
protein lattice (actin, myosin)
protein lattice (actin, myosin, titin)
power stroke
power stroke (movie)
Dystrophin-associated complex
dystrophin (importance, function)
dystrophin, dystroglycans, and sarcoglycans
correlation to diseases
in situ dystrophin
Striated muscle protein linkages
gross view
sarcomere A-band, I-band, M-line
sarcomere Z-disk
sarcolemma
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Muscle Proteins
Location
Protein
Characteristics
42 kDa, polymerizes to 7-nm thin filament
540 kDa, forms 15-nm thick filament
I, C, and T subunits
40 nm length
194-kDa dimer
actin
myosin
troponin
tropomyosin
-actinin
desmin
Z disk
vimentin
nebulin
titin
paramyosin
M line
C-protein
M-protein
merosin (laminin-2)
-dystroglycan
-dystroglycan
Transmembrane -sarcoglycan (adhalin)
-sarcoglycan
-sarcoglycan
-sarcoglycan
sarcospan
dystrophin
utrophin
Submembrane -syntrophin
-1-syntrophin
-2-syntrophin
dystrobrevin
Filaments
spans length of thin filament
3000 kDa, spans length of thick filament
140 kDa, thick filament in bundles of 200-400
165 kDa
90 kDa
153 kDa
43 kDa
50 kDa
43 kDa
35 kDa
35 kDa
?
427 kDa
430 kDa
59 kDa
59 kDa
59 kDa
87 kDa?
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Muscle Proteins
(http://www.life.uiuc.edu/crofts/bioph354/images/muscle_fibril.gif)
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Muscle Proteins
(http://www.chemsoc.org/exemplarchem/entries/kscott/images/titin.gif)
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Muscle Proteins
(http://biochem.annualreviews.org/content/vol68/issue1/images/medium/bi68_0687_1.gif)
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Power Stroke
(http://www.sci.sdsu.edu/movies/actin_myosin.html)
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Dystrophin Importance
Importance
absent in Duchenne muscular dystrophy (DMD)
reduced or altered in Becker muscular dystrophy (BMD)
deficiency in cardiac-specific form in X-linked dilated cardiomyopathy (XLDC)
Large gene and protein
2500-kb gene
14-kb mRNA (79 exons)
3685 aa
427 kDa
Localization
subsarcolemmal region in skeletal and cardiac muscle
enriched at myotendinous and neuromuscular junctions
associated with T-tubules in cardiac muscle
discontinuous distribution along membrane in smooth muscle, alternates with vinvulin
Dystrophin Function
Protein similarity
-actinins
spectrins
Functional domains
amino terminus - 240 aa, binds F-actin
coiled-coiled rod - 2400 aa, longest section provides flexibility and elasticity
cysteine-rich - 280 aa, required for membrane attachment to -dystroglycan
carboxy terminus - 420 aa, contains potential phosphorylation sites, binds to syntrophins
Function
mechanical reinforcement of sarcolemma (in skeletal muscle)
signal transduction (control of muscle fiber caliber and size)
anchor or stabilizer of dystroglycans and sarcoglycans
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Dystrophin, Dystroglycans, and Sarcoglycans
(http://med.annualreviews.org/content/vol48/issue1/images/medium/ME48_0457_1.gif)
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Correlation to Diseases
(http://www-ermm.cbcu.cam.ac.uk/0200488Xh.htm)
Striated muscle cell proteins implicated in muscular dystrophies, dilated cardiomyopathy and
lipodystrophy, and their protein–protein interactions. Myopathies, cardiomyopathy or lipodystrophy
known to be caused by particular proteins are indicated in parentheses (red). Spanning the plasma
membrane (sarcolemma) of a striated muscle cell (myoblast) is the dystrophin–glycoprotein complex
(DGC; bracketed), which provides structural integrity to the cell by crosslinking the cytoskeleton (via actin)
to the extracellular matrix (via laminin b1). Mutations in dystrophin cause Duchenne muscular dystrophy
(DMD) and mutations in the sarcoglycoproteins cause a variety of limb-girdle muscular dystrophies
(LGMD) including 2C, 2D, 2E and 2F. Desmin and actin filaments crosslink the nucleus, sarcomere and
sarcolemma. The sarcomere is the structure responsible for muscle contraction, and contains the proteins
actin, myosin, titin and telethonin. The muscle LIM protein (MLP; LIM is the term given to a protein–
protein interaction domain containing a double zinc finger motif) is a cytoskeletal binding partner of betaspectrin, itself a cytoskeletal protein. Mutations in lamin A/C can cause LGMD-1B. Other disease
abbreviations: AD-EDMD, autosomal dominant Emery–Dreifuss muscular dystrophy; X-EDMD, X-linked
EDMD; FPLD, familial Dunnigan-type partial lipodystrophy; CMD, congenital muscular dystrophy; DCM,
dilated cardiomyopathy; CMT2, Charcot–Marie–Tooth disorder type 2. The question mark indicates
uncertainty as to whether F-actin enters the nucleus from the cytoplasm.
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In situ Staining for Dystrophin
(http://www.emedicine.com/neuro/topic670.htm#section~pictures)
Muscle tissue samples are stained with specific antibodies for dystrophin. From left to
right, the panels represent (A) normal dystrophin staining; (B) intermediate dystrophin
staining in a patient with Becker muscular dystrophy; and (C) absent dystrophin staining
in a patient with Duchenne dystrophy.
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Cytoskeletal Linkages
(http://cellbio.annualreviews.org/cgi/content/full/18/1/637)
A schematic overview of cytoskeletal linkages in striated muscle (modified from
Carlsson & Thornell, 2001). The sarcomeres contain four filament systems: actin-thin,
myosin-thick, titin, and nebulin filaments. The borders of individual sarcomeres are the
Z-lines, which are precisely aligned and laterally associated with intermediate filament
proteins (such as desmin) and other cytoskeletal proteins (such as plectin). The
intermediate filaments and associated proteins also may link the peripheral myofibrils to
costameres at the sarcolemma (the muscle membrane), to mitochondria, and to the
nuclear membrane. Although many of the detailed interactions are not yet known, these
linkages are responsible for the mechanical integration and stability of myofibrils,
organelles, and membrane components for effective force transmission. The microtubule
system is not depicted in the schematic because it is unclear how they are arranged in
striated muscle; however, they may be linked to myofibrils and intermediate proteins
through proteins such as plakin family members.
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Molecular Model of Sarcomere
(http://cellbio.annualreviews.org/cgi/content/full/18/1/637)
Molecular model of the I-band, A-band, and M-line regions of the sarcomere. Polar thin
filaments, containing actin, tropomyosin, troponins C, I, and T, and single molecules of
skeletal muscle nebulin, span the I-band and interdigitate with the myosin (thick)
filaments in the A-band, where they are capped at their pointed ends by tropomodulin.
The myosin heads extend from the core of the thick filaments in the C-zone of the Aband, and are anchored and aligned in the middle of the sarcomere, the M-line. Myosinbinding proteins, including MyBP-C, are associated with the thick filaments and likely
play multiple roles in the sarcomere. Single molecules of the giant protein titin extend an
entire half sarcomere and are proposed to function as a template for sarcomere assembly.
Titin's I-band region contains elastic elements that contribute to the passive force of
myofibrils. The M-line proteins myomesin and M-protein, as well as MyBP-C, likely
contribute to the linkage of thick filaments with titin, whereas MURF-1 and p94 may
function in titin M-line region protein turn-over. Also shown here is Novex-3, a novel
mini-titin, that binds to another giant protein, obscurin. Other novel titin isoforms have
been found that are not shown here. Components whose binding sites are unknown are
shown with question marks.
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Molecular Model of Sarcomere
(http://cellbio.annualreviews.org/cgi/content/full/18/1/637)
Molecular model of sarcomeric Z-disk components, which form the borders of individual
sarcomeres. Opposing thin filaments and individual titin molecules interdigitate at the Zline and are cross-linked by {alpha}-actinin dimers. The diagram depicts one {alpha}actinin dimer simultaneously cross-linking two actin filaments and two titin molecules;
other configurations are possible. Myopodin and filamin can also bind actin filaments,
but it is not clear if they actually cross-link opposing thin filaments, as indicated here. Zline-associated proteins are shown individually or with known binding partners; the twodimensional nature of the drawing prevents a full appreciation of how the proteins are
arranged with respect to each other. Proteins whose binding sites are unknown are
indicated with question marks. It is possible that some Z-line components may be
preferentially localized to the Z-line/I-band boundary (e.g., filamin, MLP) or more
prominent in the Z-lines of peripheral myofibrils.
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Sarcolemma
(http://cellbio.annualreviews.org/cgi/content/full/18/1/637)
A schematic model of the cytoskeletal filament linkages at the sarcolemma of striated muscle. Four major
cytoskeletal/membrane junctions are depicted: (a) cadherin-based linkages to actin and intermediate
filaments (desmin); (b) integrin-based focal adhesions; (c) dystroglycan complex (DGC); and (d) spectrinbased membrane cytoskeleton. The cadherin-based fascia adheren at the intercalated disc couples
neighboring cardiomyocytes (through homotypic interactions) and tethers the contractile apparatus to the
muscle termini. Desmosomes are a second cadherin-based junction that anchor desmin filaments at the
intercalated disc. Connections between intermediate filament proteins and the membrane may occur
through a plectin/{alpha}ß-crystallin complex or via an association with DGC via dystrobrevin. Integrinbased focal adhesions and the DGC act as transmembrane receptors for ECM components (e.g., laminin)
and link the extracellular surface with the actin cytoskeleton. Integrins associate with talin, {alpha}-actinin,
vinculin and N-RAP to form a strong mechanical link to actin filaments. Integrins could directly interact
with {alpha}-actinin and/or other components not depicted here to mediate a connection with actin. The
DGC consists of the transmembrane complex {alpha}/ß-dystroglycan, dystrophin, the sarcoglycans, and
other components not depicted here. Spectrin is enriched at costameres, and is an important component of
the membrane cytoskeleton. It is linked to the membrane through ankyrin and probably the Na,K-ATPase
transmembrane protein. Spectrin may have an additional role in anchoring the contractile apparatus to the
membrane though an interaction with MLP. Importantly, all of these linkage complexes can bind to the
submembraneous actin ({gamma}-actin) and are probably interlinked through this association as well as
other unknown interactions.
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Metabolic Pathways
Glucose
glycolysis (TCA cycle)
glycogenolysis (TCA cycle)
Fatty acids
-oxidation (TCA cycle)
Metabolic Pathways
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Metabolic Pathways
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Metabolic Pathways
Nelson, D. L., and M. M. Cox. 2000. Lehninger principles of
biochemistry, 3rd ed., p. 604. Worth Publishers, New York.
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Role of Calcium
Muscle contraction
troponin C
Glycogen breakdown
calmodulin (activates phosphorylase b kinase)
Citric acid cycle activation
pyruvate dehydrogenase complex
isocitrate dehydrogenase
-ketoglutarate dehydrogenase
Role of Calcium
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