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A. Musarò - Study of the molecular and cellular mechanisms of sarcopenia: role of mIGF-1 and oxidative stress
In addition, our study is the first that documents how
the T-tubule might be the potential donor of membrane
that forms sequestering autophagocytic vesicle.
In fact one of the unresolved questions related to
autophagy concerns the origin of the membrane that
forms the sequestering vesicle. It has been proposed
that autophagosomes might initiate from the modification
of pre-existing structures.
In our study we documented the sequence of events
by which T-tubules, which normally run perpendicularly
(transversely) to the long axis of the fiber and
form junctions (or triads) with the SR terminal cisternae,
curved into a L-like structure that progress
to a vesicle-like structure encompassing amorphous
cellular material.
Thus, our study is the first to 1) establish skeletal
muscle as a primary target for the dominant action
of inherited SOD1 mutations, 2) implicate oxidative
stress as the primary trigger of muscle atrophy
associated with SOD1 mutation, 3) disjoin
muscle atrophy and function from motor neuron
degeneration.
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We are currently analyzing the role of the growth
factor mIGF-1 in ameliorating the disease in this
new mouse model. Our working hypothesis is that
mIGF-1 counteracts muscle wasting by the modulation
of proteolytic systems and oxidative pathways,
thus preserving the functional connection between
muscle and nerve.
The characterization of this new mouse model
promises to significantly advance our understanding
of the possible pathogenic mechanisms that lead to
muscle wasting in human diseases and offers novel
approaches for treatment of diseases associated with
oxidative stress accumulation.
Selected publications
Dobrowolny G, Aucello M, Rizzuto E, Beccafico S,
Mammucari C, Bonconpagni S, Belia S, Wannenes F,
Nicoletti C, Del Prete Z, Rosenthal N, Molinaro M,
Protasi F, Fanò G, Sandri M, Musarò A. Skeletal
muscle is a primary target of SOD1G93A-mediated
toxicity. Cell Metab. 2008. 8:425-36.