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Intact single muscle fibres from SOD1(G93A) amyotrophic lateral sclerosis mice display preserved specific force, fatigue resistance and training-like adaptations
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; School of Kinesiology and Health Sciences, York University, Toronto, Canada.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Örebro universitet, Institutionen för hälsovetenskaper. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.ORCID-id: 0000-0002-5322-4150
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Sports Science and Innovation Institute, Lithuanian Sports University, Kaunas, Lithuania.
Vise andre og tillknytning
2019 (engelsk)Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 597, nr 12, s. 3133-3146Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Key points:

  • How defects in muscle contractile function contribute to weakness in amyotrophic lateral sclerosis (ALS) were systematically investigated.
  • Weakness in whole muscles from late stage SOD1G93A mice was explained by muscle atrophy as seen by reduced mass and maximal force.
  • On the other hand, surviving single muscle fibres in late stage SOD1G93A have preserved intracellular Ca2+ handling, normal force-generating capacity and increased fatigue resistance.
  • These intriguing findings provide a substrate for therapeutic interventions to potentiate muscular capacity and delay the progression of the ALS phenotype.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of motor neurons, leading to severe muscle weakness and paralysis. The SOD1G93A mouse model of ALS displays motor neuron degeneration and a phenotype consistent with human ALS. The purpose of this study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles. In the current study, motor neuron loss and decreased force were evident in whole flexor digitorum brevis (FDB) muscles of mice in the late stage of disease (125–150 days of age). However, in intact single muscle fibres, specific force, tetanic myoplasmic free [Ca2+] ([Ca2+]i), and resting [Ca2+]i remained unchanged with disease. Fibre-type distribution was maintained in late-stage SOD1G93A FDB muscles, but remaining muscle fibres displayed greater fatigue resistance compared to control and showed increased expression of myoglobin and mitochondrial respiratory chain proteins that are important determinants of fatigue resistance. Expression of genes central to both mitochondrial biogenesis and muscle atrophy where increased, suggesting that atrophic and compensatory adaptive signalling occurs simultaneously within the muscle tissue. These results support the hypothesis that muscle weakness in SOD1G93A is primarily attributed to neuromuscular degeneration and not intrinsic muscle fibre defects. In fact, surviving muscle fibres displayed maintained adaptive capacity with an exercise training-like phenotype, which suggests that compensatory mechanisms are activated that can function to delay disease progression.

sted, utgiver, år, opplag, sider
Cambridge University Press, 2019. Vol. 597, nr 12, s. 3133-3146
Emneord [en]
Amyotrophic lateral sclerosis, Muscle fatigue, Cytosolic calcium, Force, Muscle adaptation
HSV kategori
Identifikatorer
URN: urn:nbn:se:oru:diva-74237DOI: 10.1113/JP277456ISI: 000474245500011PubMedID: 31074054Scopus ID: 2-s2.0-85066899665OAI: oai:DiVA.org:oru-74237DiVA, id: diva2:1315654
Forskningsfinansiär
Swedish Research Council, 2016-02112Swedish Society for Medical Research (SSMF), S16-0159Swedish Heart Lung Foundation, 20160741 20180803Wenner-Gren Foundations
Merknad

Funding Agencies:

Swedish Research Council for Sports Science  FO2018-0019 

Lars Hierta Minne Foundation  FO2015-0510 

Jeansson Foundation  

Stockholm County Council (ALF) 

Tilgjengelig fra: 2019-05-14 Laget: 2019-05-14 Sist oppdatert: 2019-11-13bibliografisk kontrollert

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