Download Does skeletal muscle fiber branching play a role in the inability of

J Appl Physiol 112: 331, 2012;
doi:10.1152/japplphysiol.01355.2011.
Letter To The Editor
Does skeletal muscle fiber branching play a role in the inability of old EDL
dystrophic muscle to resist large passive stretches?
Stewart Head
Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
TO THE EDITOR:
Address for reprint requests and other correspondence: S. Head, Dept. of
Physiology, School of Medical Sciences, Univ. of New South Wales, Sydney,
2502 NSW, Australia (e-mail: [email protected]).
http://www.jap.org
branched fibers and a 60% force deficit in old EDL mdx
muscles, where over 90% of fibers show some degree of
branching. Further evidence that it was the fiber branching
itself and not the absence of dystrophin that resulted in muscle
weakness and breakage was obtained using the skinned fiber
technique. When a single isolated mdx muscle fiber was tied up
with a branch between the points of attachment it broke, then
when the same muscle fiber was reattached with no branch
point between the attachments, it could sustain maximal isometric force without breaking (4). This is evidence that the
breakage is a result of branching and not some other intrinsic
weakness. In the study by Hakim et al. (3), by 14 –20 mo nearly
100% of mdx EDL fibers would have extensive branching and
I would suggest this makes a significant contribution to the
muscle tearing, in addition to the increase in stiffness mechanism proposed by the authors (3).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
Author contributions: S.I.H. interpreted results of experiments; S.I.H.
drafted manuscript; S.I.H. edited and revised manuscript; S.I.H. approved final
version of manuscript.
REFERENCES
1. Chan S, Head SI. The role of branched fibers in the pathogenesis of
Duchenne muscular dystrophy. Exp Physiol 96: 564 –571, 2011.
2. Chan S, Head SI, Morley JW. Branched fibers in dystrophic mdx muscle
are associated with a loss of force following lengthening contractions. Am
J Physiol Cell Physiol 293: C985–C992, 2007.
3. Hakim CH, Grange RW, Duan D. The passive mechanical properties of
the extensor digitorum longus muscle are compromised in 2- to 20-mo-old
mdx mice. J Appl Physiol 110: 1656 –1663, 2011.
4. Head SI. Branched fibers in old dystrophic mdx muscle are associated with
mechanical weakening of the sarcolemma, abnormal Ca2⫹ transients and a
breakdown of Ca2⫹ homeostasis during fatigue. Exp Physiol 95: 641–656,
2010.
5. Head SI. A two stage model of skeletal muscle necrosis in muscular
dystrophy; the role of fiber branching in the terminal stages. In Muscular
Dystrophy, edited by Hegde M. Rijeka, Croatia: InTech Open Access, 2011.
6. Head SI, Williams DA, Stephenson DG. Abnormalities in structure and
function of limb skeletal muscle fibers of dystrophic mdx mice. Proc Biol
Sci 248: 163–191, 1992.
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Hakim et al. (3) examined the passive mechanical properties of fast-twitch extensor digitorum longus (EDL)
muscles from young and old mdx dystrophic mice. They
elegantly showed that by increasing passive strain on the
dystrophic muscle from 110% of optimal length (Lo) to 160%
of Lo, the muscle physically ruptured in a manner that got
progressively worse with age. At the oldest age points tested,
14 and 20 mo, the dystrophic muscles pulled apart. Importantly, in age matched dystrophin positive controls, this pulling
apart of the muscle did not occur. The authors (3) propose that
one reason for this dramatic tearing of the dystrophic muscle
with age is due to increased fibrosis and muscle stiffness.
Undoubtedly, increasing stiffness with age would play a role in
dystrophic damage. However, I suggest that the widely reported age-related increase in the number of branched skeletal
muscle fibers present within the dystrophic muscle will also
make a significant contribution (1, 2, 4 – 6). It is not the absence
of dystrophin, in itself, that is weakening the muscle; as it is
absent from both young and old mdx muscles. There must be
some additional age-related factor or factors at play. The paper
by Hakim et al. (3) demonstrates that ageing in itself is not one
of these factors. To further interpret the findings of Hakim et al.
(3), I propose that the production of branched fibers in ageing
dystrophic muscle contributes to the increase susceptibility to
damage (1). As the dystrophic disease progresses, one of the
most striking features of the skeletal muscle pathology in the
dystrophinopathies is the appearance of abnormal, branched,
skeletal muscle fibers (6). These branched fibers have been
widely reported in humans with Duchenne muscular dystrophy, where the number of branched fibers has been correlated
with the severity of the disease (5). Earlier work from my
laboratory has shown that there is a strong correlation between
the appearance of branched fibers in the mdx mouse and the
susceptibility of EDL muscle to eccentric damage (2). In this
work we showed a mild eccentric contraction produced no
damage in EDL muscle from young mdx mice with very few