Ecoclimber
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Premission to repost by Prof.Gavin Giovannoni
There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.
Mitochondrial dysfunction linked to neurodegeneration in MS
"Energetics; the new buzz word in MS. There is mounting evidence that malfunction of mitochondria contributes to neurodegeneration in MS. The mitochondria are the energy factories of the cells and generate much needed energy for nerve conduction and to maintain the integrity of axons and neurons.
In addition, mitochondria have the ability to signal to the cell to commit suicide. When mitochondria are not working very well the cell has to generate energy without using oxygen. This results in the production of lactic acid.
The study below shows that lactic acid detected in the peripheral blood of MSers correlates with neurodegeneration in the retina. The investigators imply in their conclusions that this may be causal, i.e. the mitochondrial dysfunction may be causing the neurodegeneration.
Playing devil's advocate it may be the other way round; could neurodegeneration be causing mitochondrial dysfunction?
As cells die they trigger local innate immune reactions via complex cell sensing mechanisms. Some of these mechanisms produce mediators that then lead to secondary mitochondrial dysfunction. This is called reverse causation. To dissect out these two hypotheses we need to treat MS with drugs that enhance mitochondrial function or protect them and see if it improves MS and/or delays MS disease progression. In fact we have included a novel drug class in our recent funding application to the progressive MS alliance."
Epub: Petzold et al. Visual pathway neurodegeneration winged by mitochondrial dysfunction. Ann Clin Transl Neurol. 2015;2(2):140-50. doi: 10.1002/acn3.157.
OBJECTIVES:
To test for structural and functional contribution of mitochondrial dysfunction to neurodegeneration in multiple sclerosis (MS). A visual pathway model void of MS lesions was chosen in order to exclude neurodegeneration secondary to lesion related axonotmesis.
METHODS:
A single-centre cohort study (230 MS patients, 63 controls). Spectral domain optical coherence tomography of the retina, 3T magnetic resonance imaging of the brain, spectrophotometric assessment of serum lactate levels. Postmortem immunohistochemistry.
RESULTS:
The visual pathway was void of MS lesions in 31 patients and 31 age-matched controls. Serum lactate was higher in MS compared to controls (P = 0.029). High serum lactate was structurally related to atrophy of the retinal nerve fiber layer at the optic disc (P = 0.041), macula (P = 0.025), and the macular ganglion cell complex (P = 0.041). High serum lactate was functionally related to poor color vision (P < 0.01), Expanded Disability Status Scale score (R = 0.37, P = 0.041), Guy's Neurological disability score (R = 0.38, P = 0.037), MS walking scale (R = 0.50, P = 0.009), upper limb motor function (R = 0.53, P = 0.002). Immunohistochemistry demonstrated increased astrocytic expression of a key lactate generating enzyme in MS lesions as well as profound vascular expression of monocarboxylate transporter-1, which is involved in lactate transport.
INTERPRETATION:
This study provides structural, functional, and translational evidence for visual pathway neurodegeneration in MS related to mitochondrial dysfunction.
Mitochondria again, but this time in muscle!
Pathol Res Pract.2015 Feb 17. pii: S0344-0338(15)00027-8. doi: 10.1016/j.prp.2015.02.004. [Epub ahead of print]Skeletal muscle findings in experimental autoimmune encephalomyelitis.
Luque E, Ruz-Caracuel I, Medina FJ, Leiva-Cepas F, Agüera E, Sánchez-López F, Lillo R, Aguilar-Luque M, Jimena I, Túnez I,Peña J.
INTRODUCTION:
Skeletal muscle is a target organ in multiple sclerosis, a chronic debilitating disease of the central nervous system caused by demyelination and axonal deterioration.
Since the experimental autoimmune encephalomyelitis model reproduces the relapsing-remitting course found in most multiple sclerosis patients, this model was used to compare the histological features of skeletal muscle at onset with those observed at the start of the second relapse.
MATERIAL AND METHODS:
Histological, histochemical and ultrastructural changes, as well as biochemical oxidative damage and antioxidant-system markers, were examined in the soleus and extensor digitorum longus muscles of Dark Agouti rats in which experimental autoimmune encephalomyelitis had been induced by active immunization using myelin oligodendrocyte glycoprotein.
RESULTS:
Histological examination at disease onset revealed ragged-red fibers and ultrastructural evidence of mitochondrial degeneration. At the second relapse, neurogenic changes included a wide range of cytoarchitectural lesions, skeletal muscle atrophy and the appearance of intermediate fibers; however, differences were observed between soleus and extensor digitorum longus lesions. Biochemical tests disclosed an increase in oxidative stress markers at onset, which was more pronounced at the second relapse.
CONCLUSIONS:
Microscopic findings suggest that two patterns can be distinguished at disease onset: an initial phase characterized by muscle mitochondrial alterations, and a second phase dominated by a histological muscle pattern of clearly neurogenic origin.
This is work done in the mouse model of MS (the EAE model), and some caution should be exercised when drawing parallels with humans and with MS as a whole.
Nonetheless, these findings raise interesting questions about whether the same happens in MSers? I've sometimes wandered about this in clinic, particularly in those with disproportionate muscle wasting, in so far as to send some of them to a neurophysiologist for EMGs! [In general terms were are taught that muscle wasting is a late feature of CNS disorders but seen early in peripheral nervous system disorders, including muscle disease].
But the researchers here demonstrate three fundamental facts:
1) That the muscle is affected in the acute phase i.e. onset of the EAE disease - equivalent to a human relapse, and the changes that take place are almost exclusively related to mitochondrial dysfunction;
2) it's only at the mid-to-longterm disease phase that the muscle changes point to changes that are neurogenic in origin, i.e. caused by denervation of the muscle (from lack of axons); and
3) mitochondrial damage is linked to an increase in oxygen reactive species production (i.e. oxidative stress), which is driving force for destruction of the denervated skeletal muscle over the long-term.
Could Co-enzyme Q10 supplementation therefore become a future addition to the steroid armamentarium in an MS relapse??
There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.
Mitochondrial dysfunction linked to neurodegeneration in MS
"Energetics; the new buzz word in MS. There is mounting evidence that malfunction of mitochondria contributes to neurodegeneration in MS. The mitochondria are the energy factories of the cells and generate much needed energy for nerve conduction and to maintain the integrity of axons and neurons.
In addition, mitochondria have the ability to signal to the cell to commit suicide. When mitochondria are not working very well the cell has to generate energy without using oxygen. This results in the production of lactic acid.
The study below shows that lactic acid detected in the peripheral blood of MSers correlates with neurodegeneration in the retina. The investigators imply in their conclusions that this may be causal, i.e. the mitochondrial dysfunction may be causing the neurodegeneration.
Playing devil's advocate it may be the other way round; could neurodegeneration be causing mitochondrial dysfunction?
As cells die they trigger local innate immune reactions via complex cell sensing mechanisms. Some of these mechanisms produce mediators that then lead to secondary mitochondrial dysfunction. This is called reverse causation. To dissect out these two hypotheses we need to treat MS with drugs that enhance mitochondrial function or protect them and see if it improves MS and/or delays MS disease progression. In fact we have included a novel drug class in our recent funding application to the progressive MS alliance."
Epub: Petzold et al. Visual pathway neurodegeneration winged by mitochondrial dysfunction. Ann Clin Transl Neurol. 2015;2(2):140-50. doi: 10.1002/acn3.157.
OBJECTIVES:
To test for structural and functional contribution of mitochondrial dysfunction to neurodegeneration in multiple sclerosis (MS). A visual pathway model void of MS lesions was chosen in order to exclude neurodegeneration secondary to lesion related axonotmesis.
METHODS:
A single-centre cohort study (230 MS patients, 63 controls). Spectral domain optical coherence tomography of the retina, 3T magnetic resonance imaging of the brain, spectrophotometric assessment of serum lactate levels. Postmortem immunohistochemistry.
RESULTS:
The visual pathway was void of MS lesions in 31 patients and 31 age-matched controls. Serum lactate was higher in MS compared to controls (P = 0.029). High serum lactate was structurally related to atrophy of the retinal nerve fiber layer at the optic disc (P = 0.041), macula (P = 0.025), and the macular ganglion cell complex (P = 0.041). High serum lactate was functionally related to poor color vision (P < 0.01), Expanded Disability Status Scale score (R = 0.37, P = 0.041), Guy's Neurological disability score (R = 0.38, P = 0.037), MS walking scale (R = 0.50, P = 0.009), upper limb motor function (R = 0.53, P = 0.002). Immunohistochemistry demonstrated increased astrocytic expression of a key lactate generating enzyme in MS lesions as well as profound vascular expression of monocarboxylate transporter-1, which is involved in lactate transport.
INTERPRETATION:
This study provides structural, functional, and translational evidence for visual pathway neurodegeneration in MS related to mitochondrial dysfunction.
Mitochondria again, but this time in muscle!
Pathol Res Pract.2015 Feb 17. pii: S0344-0338(15)00027-8. doi: 10.1016/j.prp.2015.02.004. [Epub ahead of print]Skeletal muscle findings in experimental autoimmune encephalomyelitis.
Luque E, Ruz-Caracuel I, Medina FJ, Leiva-Cepas F, Agüera E, Sánchez-López F, Lillo R, Aguilar-Luque M, Jimena I, Túnez I,Peña J.
INTRODUCTION:
Skeletal muscle is a target organ in multiple sclerosis, a chronic debilitating disease of the central nervous system caused by demyelination and axonal deterioration.
Since the experimental autoimmune encephalomyelitis model reproduces the relapsing-remitting course found in most multiple sclerosis patients, this model was used to compare the histological features of skeletal muscle at onset with those observed at the start of the second relapse.
MATERIAL AND METHODS:
Histological, histochemical and ultrastructural changes, as well as biochemical oxidative damage and antioxidant-system markers, were examined in the soleus and extensor digitorum longus muscles of Dark Agouti rats in which experimental autoimmune encephalomyelitis had been induced by active immunization using myelin oligodendrocyte glycoprotein.
RESULTS:
Histological examination at disease onset revealed ragged-red fibers and ultrastructural evidence of mitochondrial degeneration. At the second relapse, neurogenic changes included a wide range of cytoarchitectural lesions, skeletal muscle atrophy and the appearance of intermediate fibers; however, differences were observed between soleus and extensor digitorum longus lesions. Biochemical tests disclosed an increase in oxidative stress markers at onset, which was more pronounced at the second relapse.
CONCLUSIONS:
Microscopic findings suggest that two patterns can be distinguished at disease onset: an initial phase characterized by muscle mitochondrial alterations, and a second phase dominated by a histological muscle pattern of clearly neurogenic origin.
This is work done in the mouse model of MS (the EAE model), and some caution should be exercised when drawing parallels with humans and with MS as a whole.
Nonetheless, these findings raise interesting questions about whether the same happens in MSers? I've sometimes wandered about this in clinic, particularly in those with disproportionate muscle wasting, in so far as to send some of them to a neurophysiologist for EMGs! [In general terms were are taught that muscle wasting is a late feature of CNS disorders but seen early in peripheral nervous system disorders, including muscle disease].
But the researchers here demonstrate three fundamental facts:
1) That the muscle is affected in the acute phase i.e. onset of the EAE disease - equivalent to a human relapse, and the changes that take place are almost exclusively related to mitochondrial dysfunction;
2) it's only at the mid-to-longterm disease phase that the muscle changes point to changes that are neurogenic in origin, i.e. caused by denervation of the muscle (from lack of axons); and
3) mitochondrial damage is linked to an increase in oxygen reactive species production (i.e. oxidative stress), which is driving force for destruction of the denervated skeletal muscle over the long-term.
Could Co-enzyme Q10 supplementation therefore become a future addition to the steroid armamentarium in an MS relapse??
