Molecular structure and function of Skeletal Muscle

The skeletal muscle groups of the mammalian body are made up of bundles of
muscle fibers. These fibers can be assigned to different identity classifications
("Types"), with characteristic movement rates, response to neural inputs, and
metabolic styles
Skeletal muscle fibers are classified into fiber types, in particular slow twitch
versus fast twitch.
Muscle fiber types are generally defined by the particular myosin heavy chain
isoforms that they express, but many other components contribute to a fiber’s
physiological characteristics.
Skeletal muscle fiber type can have a profound impact on muscle diseases,
including-
1) Certain muscular dystrophies and sarcopenia,
2) The aging-induced loss of muscle mass and strength.
In mammalian skeletal muscles, multiple fiber types are generally intermingled within a
single muscle group, and different muscle groups have varying proportions of fiber types.
For example, the human soleus leg muscle is predominantly type 1 fibers, whereas the
triceps arm muscle is predominantly type 2.
These proportions are plastic, however, and muscle fibers have the ability to remodel their
phenotypes to help muscles adapt to different use.
For example, endurance exercise training can induce a modestly increased
proportion of type 1 fibers.
Conversely, disease states such as obesity are also associated with altered
proportions of fiber types.
The diversity in contraction physiology and metabolic activity of different fiber types, along
with fiber-type plasticity, not only provide for a wide range of functions but also provide
differential susceptibility to certain muscle diseases.
Based on differential myosin heavy chain (MYH) gene expression, there is further
classification of fast-twitch fibers into three major subtypes types 2A, 2X, and 2B
(although humans do not appear to have MYH4-expressing type 2B fibers).

Hybrid MYH expression in different fibers of a muscle group can allow for even more
subtypes (1/2A, 2A/2X, 2X/2B), resulting in an almost continuous range of ATP usage and
muscle contraction speeds, from the fastest (type 2B) to the slowest (type 1)
Skeletal muscle fibers also vary in energy production. Type 1 and 2A fibers primarily use
oxidative metabolism, and type 2X and 2B fibers primarily rely upon glycolytic metabolism.
In addition to MYH expression and cellular metabolism programs, factors contributing to
fiber-type identities include multiple components of the sarcomere contractile machinery,
such as fast and slow tropomyosin isoforms
Duchenne muscular dystrophy—Duchenne muscular dystrophy (DMD) is the most common
childhood muscular dystrophy; this disease is caused by mutations in the DMD gene that
encodes dystrophin. In human limb muscle samples, Type2 fibers (then referred to as type
2B, but likely type 2X) are the first fibers to degenerate and are eventually lost in DMD
patients, whereas type 1 fibers are affected relatively late.
Facioscapulohumeral muscular dystrophy—Facioscapulohumeral muscular dystrophy
(FSHD) is a progressive muscular dystrophy characterized by weakness and wasting of the
facial, shoulder and upper arm muscles. FSHD is strongly associated with, and likely caused
by, aberrant activation of DUX4, which encodes a double homeobox transcription factor that
is normally repressed in skeletal muscle.
Myotonic dystrophy—The myotonic dystrophies Type 1 and Type 2 (DM1 and DM2) are
among the most common adult-onset muscular dystrophies. They share clinical phenotypes
including multisystem involvement, muscle atrophy, and muscle weakness. Both types of
myotonic dystrophies are caused by microsatellite expansions.
Congenital fiber type disproportion—Congenital fiber type disproportion (CFTD) is a
congenital myopathy that is diagnosed when type 1 fibers are found in predominant
proportions, are consistently much smaller than type 2 fibers, and there is no other
histologic muscle structural abnormality.
Myosinopathies—Myosinopathies are muscle diseases caused by mutations in myosin
heavy chain genes; certain myosinopathies show atrophy of specific fiber types.
Pompe disease—Pompe disease is a glycogen storage disease caused by defects in acid
alpha-glucosidase (GAA)39. With deficiency or absence of GAA, glycogen accumulates in
lysosomes, leading to lysosome swelling, blocking of lysosome-autophagosome fusion, and
accumulation of autophagic vesicles. Skeletal and cardiac muscle is most affected by Pompe
disease. Loss of GAA activity leads to the infantile form, which presents severe muscle
weakness and fatal hypertrophic cardiomyopathy. Partial loss of GAA activity leads to later
onset of progressive skeletal muscle weakness.
Obesity and type 2 diabetes—Obesity and type 2 diabetes are characterized by severe
insulin resistance in skeletal muscle1,2 . Obese individuals and individuals with type 2
diabetes both show reduced proportions of type 1 fibers and increased proportions of type
2X fibers.
Muscle inactivity—Loss of or reduced muscle use has been shown to cause significant
atrophy of all muscle fiber types but particularly of type 1 fibers, accompanied by a
fibertype shift from type 1 and 2A fibers to type 2X.
Aging/sarcopenia—The loss of skeletal muscle mass and strength due to aging, called
sarcopenia, is characterized by a selective reduced size and greater atrophy of type 2 fibers.
These effects on fiber type morphology correlate with reduced expression of MYH2 (type
2A) and MYH1 (type 2X), whereas MYH7 (type 1) expression was not affected.

Heart failure and COPD—Diseases such as chronic heart failure and chronic obstructive
pulmonary disease (COPD) can lead to systemic effects on peripheral skeletal muscle.
Patients with chronic heart failure and COPD, limb muscle exhibits a shift in fiber
type proportions, from type 1 to type 2, with corresponding changes in MYH
expression. These changes are similar to those seen in muscle inactivity disorder.s
 ‘‘exercise is medicine’’
Worldwide, approx imately one in three adults and four in five adolescents do not achieve
the recommended quantity and quality of daily exercise.
Current public health recommendations recognize regular exercise and physical activity as a
cornerstone in the prevention, management, and treatment of numerous chronic
conditions, including hypertension, coronary heart disease, obesity, type 2 diabetes mellitus
(T2DM), and age-related muscle wasting (sarcopenia).
For instance, short-term exercise training partially reverses the progression of metabolic
disease, whereas lifestyle interventions incorporating increased physical activity remain the
primary preventive approach for metabolic disease. In fact, regular exercise combined with
dietary intervention is more successful than pharmacological intervention in the treatment
and prevention of T2DM and sarcopenia.
The Molecular Basis of Adaptation to Exercise Schematic representation of changes in mRNA expression (bottom
panel) and protein content (middle panel) over time as a consequence of acute exercise and chronic (repetitive)
exercise training. Although each individual bout of exercise is necessary as a stimulus for adaptation, it alone is
insufficient to alter the muscle phenotype—training-induced phenotypic adaptation is the consequence of
repetition of the stimulus of individual exercise bouts. In order for a gene upregulated by exercise and training, an
individual exercise bout elicits a rapid, but transient, increase in relative mRNA expression of a given gene during
recovery. Alterations in mRNA expression several-fold from basal levels are typically greatest at 3–12 hr after
cessation of exercise and generally return to basal levels within 24 hr. Translational processing and an elevated rate
of postexercise protein synthesis result in a modest, same-directional change in protein content. Superimposition
of repeated exercise bouts results in the gradual accumulation of protein in response to repeated, pulsed
increases in relative mRNA expression. Thus, long-term adaptation to training is due to the cumulative effects of
each acute exercise bout leading to a new functional threshold.
Defects in thin filament proteins that cause myopathies
Nemaline myopathy – the myopathy of the thin filament: Mutations in many components of the
thin filament cause a subtype of congenital myopathy called nemaline myopathy.
Nebulin and NEB related NM: NEB encodes for nebulin, one of the largest proteins in the human
genome. Nebulin is composed primarily of a repeat structure characterized by a series of actin
binding domains interspersed with tropomyosin binding domains. A growing body of evidence
supports that the main function of nebulin is to serve as a molecular ruler that dictates the length
of the thin filament. Since muscle force is generated through the interaction between thick and
thin filaments, there is a tight correlation between actin filament length and force generation;
thus, loss of nebulin results in reduced contractile force and muscle weakness. Nebulin has
additional functions including regulating actin/myosin cross bridging and participating in signaling
pathways critical for actin filament formation.
Disorders of the myosin heavy chain—Myosin heavy chains form homodimers that function as
the main action component of the thick filament. They have a globular head domain that
interacts directly with actin and has ATPase activity, and a distal rod domain important for
dimerization and other protein-protein interactions. Of the 8 myosin heavy chains (MyHCs) found
in skeletal muscle, mutations in 4 genes (MYH2, MYH3, MYH7, and MYH8) are associated with
muscle disease (arthrogryposis, a condition characterized by multiple joint contractures present
from birth)
Titin and TTNopathies—TTN encodes the giant myofilament protein titin, one of the largest
and most complex proteins in the human genome. Titin spans from the Z-disc (at its N
terminus) to the M line, so is essentially the length of one half of the sarcomere
(approximately 1 μM). It is laid down early in development and is believed to be a template
for sarcomere formation.
Titin has myriad functions in skeletal muscle, the most important and well-studied of which
are its roles as a molecular spring, as a generator of passive stiffness for the myofiber, and as
a regulator of actin contractile force generation.