Muscle pathology in a mouse model of amyotrophic lateral sclerosis.
Doctoral thesis, UCL (University College London).
Recent evidence has shown that non-neuronal cells within the CNS play a role in motoneuron degeneration in ALS. However, while it is accepted that various muscles are differentially affected within the disease, it is still unclear whether muscle has a causal role in ALS. In this Thesis, using a mouse model of ALS (mutant SOD1 transgenic mice), I examined muscle and NMJ pathology in two different muscle types, at various stages of disease progression. Using morphological and functional markers of innervation, I found that mSOD1- mediated pathology was present in fast-twitch muscles of mSOD1 mice prior to motoneuron degeneration. This occurred at a time when slow-twitch muscles remain innervated. This difference in the vulnerability of fast-twitch and slow-twitch muscles to disease was reflected in a differential heat shock response (HSR), with the slow-twitch soleus muscle displaying higher heat shock protein (hsp) levels over a longer duration of disease than the fast-twitch TA muscle. Equally, examination of the NOS response revealed a significant difference in nNOS expression between the fast-twitch TA and slow-twitch soleus muscles. Furthermore, fast-twitch muscles from mSOD1 mice also demonstrated greater vulnerability to cell stress such as glucose deprivation and caffeine stress in vitro. This Thesis also examined the effect of treatment with Arimoclomol, a pharmacological co-inducer of the HSR, on muscle and NMJ pathology. I found that treatment with was sufficient to decrease muscle pathology, augment the HSR and reduce mSOD1-meditated changes in nNOS expression. These findings support previous suggestions that targeting the periphery, in conjunction with the CNS, is an effective therapeutic strategy against ALS. Furthermore, that Arimoclomol’s previously reported beneficial effects are due, at least in part, to its effect in the periphery.
|Title:||Muscle pathology in a mouse model of amyotrophic lateral sclerosis|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Motor Neuroscience and Movement Disorders|
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