PMID- 29666144 OWN - NLM STAT- MEDLINE DCOM- 20181001 LR - 20181114 IS - 1754-8411 (Electronic) IS - 1754-8403 (Print) IS - 1754-8403 (Linking) VI - 11 IP - 4 DP - 2018 Apr 16 TI - Sporadic amyotrophic lateral sclerosis (SALS) - skeletal muscle response to cerebrospinal fluid from SALS patients in a rat model. LID - 10.1242/dmm.031997 [doi] LID - dmm031997 AB - Skeletal muscle atrophy is the most prominent feature of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease of motor neurons. However, the contribution of skeletal muscle to disease progression remains elusive. Our previous studies have shown that intrathecal injection of cerebrospinal fluid from sporadic ALS patients (ALS-CSF) induces several degenerative changes in motor neurons and glia of neonatal rats. Here, we describe various pathologic events in the rat extensor digitorum longus muscle following intrathecal injection of ALS-CSF. Adenosine triphosphatase staining and electron microscopic (EM) analysis revealed significant atrophy and grouping of type 2 fibres in ALS-CSF-injected rats. Profound neuromuscular junction (NMJ) damage, such as fragmentation accompanied by denervation, were revealed by alpha-bungarotoxin immunostaining. Altered expression of key NMJ proteins, rapsyn and calpain, was also observed by immunoblotting. In addition, EM analysis showed sarcolemmal folding, Z-line streaming, structural alterations of mitochondria and dilated sarcoplasmic reticulum. The expression of trophic factors was affected, with significant downregulation of vascular endothelial growth factor (VEGF), marginal reduction in insulin-like growth factor-1 (IGF-1), and upregulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). However, motor neurons might be unable to harness the enhanced levels of BDNF and GDNF, owing to impaired NMJs. We propose that ALS-CSF triggers motor neuronal degeneration, resulting in pathological changes in the skeletal muscle. Muscle damage further aggravates the motor neuronal pathology, because of the interdependency between them. This sets in a vicious cycle, leading to rapid and progressive loss of motor neurons, which could explain the relentless course of ALS.This article has an associated First Person interview with the first author of the paper. CI - (c) 2018. Published by The Company of Biologists Ltd. FAU - Shanmukha, Shruthi AU - Shanmukha S AUID- ORCID: 0000-0001-5659-2250 AD - Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India. FAU - Narayanappa, Gayathri AU - Narayanappa G AD - Department of Neuropathology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India. FAU - Nalini, Atchayaram AU - Nalini A AD - Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India. FAU - Alladi, Phalguni Anand AU - Alladi PA AUID- ORCID: 0000-0002-2876-3478 AD - Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India trraju.nimhans@gmail.com alladiphalguni@gmail.com. FAU - Raju, Trichur R AU - Raju TR AUID- ORCID: 0000-0002-7742-4050 AD - Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India trraju.nimhans@gmail.com alladiphalguni@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180416 PL - England TA - Dis Model Mech JT - Disease models & mechanisms JID - 101483332 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (Vascular Endothelial Growth Factor A) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Amyotrophic Lateral Sclerosis/*cerebrospinal fluid/pathology MH - Animals MH - Animals, Newborn MH - Atrophy MH - Brain-Derived Neurotrophic Factor/metabolism MH - Disease Models, Animal MH - Down-Regulation MH - Glial Cell Line-Derived Neurotrophic Factor/metabolism MH - Humans MH - Insulin-Like Growth Factor I/metabolism MH - Muscle, Skeletal/*pathology MH - Neuromuscular Junction/pathology MH - Oxidative Stress MH - Rats, Wistar MH - Sarcolemma/pathology/ultrastructure MH - Up-Regulation MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC5963857 OTO - NOTNLM OT - Amyotrophic lateral sclerosis OT - Electron microscopy OT - Immunohistochemistry OT - Muscle atrophy OT - NMJ OT - Trophic factors COIS- Competing interestsThe authors declare no competing or financial interests. EDAT- 2018/04/19 06:00 MHDA- 2018/10/03 06:00 PMCR- 2018/04/16 CRDT- 2018/04/19 06:00 PHST- 2017/09/12 00:00 [received] PHST- 2018/03/05 00:00 [accepted] PHST- 2018/04/19 06:00 [entrez] PHST- 2018/04/19 06:00 [pubmed] PHST- 2018/10/03 06:00 [medline] PHST- 2018/04/16 00:00 [pmc-release] AID - 11/4/dmm031997 [pii] AID - DMM031997 [pii] AID - 10.1242/dmm.031997 [doi] PST - epublish SO - Dis Model Mech. 2018 Apr 16;11(4):dmm031997. doi: 10.1242/dmm.031997.