di
Anna Giulia Cattaneo
Dipartimento di Scienze Biochimiche e Molecolari (DBSM), Università
dell'Insubria, Varese.
The loss of mass and strength of skeletal muscle is frequently
seen at all ages as a consequence of injuries and prolonged
inactivation, for example following bone fractures, nerve
injuries or invalidating illnesses. Nevertheless this condition
dramatically rises in frequency and severity in aged people,
even if still in good general health. The term sarcopenia
was introduced to depict this conditions, in which a specific
defect of type II myofibres and of their satellite cells has
been described, not seen for example in sporadic mitochondrial
myopathies. The central role of satellite cells in this condition
will be discussed later.
A comprehensive description of this defect is still lacking:
among the traditional methods to study muscle mass and strength,
dynamometry is the most affordable and reliable, but it is
not informative about the muscle mass and the physiopathology
of sarcopenia. A quite large number of trials are ongoing:
the ClinicalTrials.gov, a register developed by U.S. Authorities
but worldwide accessible, collect at the present 48 protocols
on sarcopenia, 23 of them still recruiting patients. Most
of them are both descriptive and interventional, i.e. proposing
some kind of treatment. However the methods used to test muscle
function are often expensive, like those using stable or radioactive
isotopes, resonance imaging, and dual X-ray absorptiometry
or near infrared spectroscopy. Nevertheless, these studies
are very important to assess the minimal requirements for
functional investigation.
More recently, histological finding associated with the assessment
of skeletal muscle proteome shed new light on basic mechanisms
operating during sarcopenia development and its recovery.
Several proteomic predictors of recovery after resistance
training (RT) have been identified: the ciliary neutrotrophic
factor, the matrix metallo-proteinase-2, the TIMP-1 and the
insulin-like growth factor-1, between others. Other mRNA,
expressing proteins involved in immune and stress response,
or in the control of cell cycle, have been found to be enhanced
after a high intensity resistance loading, a type of exercise
inducing a modest muscle damage. These markers were not modified,
however, after RT. Resistance training (RT) instead expands
the mitochondrial network in young individuals, not in aged
sarcopenic subjects, in which mutations and deletions of mitochondrial
DNA are observed only in type II myocytes, not in satellite
cells.
Satellite cells seem to play the most important role in sarcopenia
and in recovery of skeletal muscle function in elderly. These
cells, also called muscle stem cells, represent a reservoir
of nuclei for type II myofibres, i.e. they are responsible
of regenerative responses in muscle. Their differentiation
into fusion-competent myoblasts is regulated by the interplay
of gene families WNT and Notch, originally identified in Drosophila
but with homologs in mammals and humans. The former induces
stem cell differentiation, the latter controls the proliferation
and inhibiting WNT. The regulatory role of Notch influences
also the expression of other genes involved in apoptosis and
inflammation, and this recall the role of inflammatory and
stress markers described in the previous paragraph.
Resistance training (RT) restores in older subjects both
the number satellite cells and the size of type II myofibres,
if sufficiently prolonged and sustained to improve skeletal
muscle function. A recent, comprehensive and innovative work
(EMBO Molecular Medicine 2009, doi: 10.1002/emmm.200900045)
demonstrates that recovery after 2 weeks immobilization of
a muscular district is near to complete after 3 weeks retraining
in younger volunteers. Histology from muscle biopsies clearly
shows the higher reaction of the connective and inflammatory
components in muscles from older, while healthy, individuals.
While still maintained and able to react normally when isolated
"in vitro", satellite cells cannot repair the injured
muscle. The stem muscle cells from aged persons, however,
are functionally intact when isolated "in vitro"
in the absence of aged muscle components, while those from
young persons are inhibited in the presence of products of
aged muscles. The experimental finding that aged muscle are
over expressing genes products able to inhibit Notch explains,
according to the Authors, their poor recovery after immobilization.
Data from this newer approach in investigating the skeletal
muscle function, decline and recovery late in life seems to
open not only newest and deepest explanation for a condition
poorly understood until now, but they open even new perspectives
to an early detection of subject at risk and prognosis. In
a near future these new findings could be even of importance
in posing the basis for more efficient treatment of this frequent
condition.
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