The role of skeletal muscle in the initiation and progression of knee osteoarthritis

Tonge, Daniel Paul (2010) The role of skeletal muscle in the initiation and progression of knee osteoarthritis. PhD thesis, University of Nottingham.

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It is established that patients with knee osteoarthritis (OA) exhibit marked muscle weakness, one of the most frequent and earliest reported symptoms associated with knee OA. Weakness primarily affects the quadriceps muscle with little evidence of hamstring involvement. Traditionally, muscle weakness has been considered a secondary effect in knee OA, resulting from disuse of the affected joint due to the presence of pain and/or inflammation, and therefore has received little attention with regards to its involvement in the initiation or progression of OA. However, there is clinical evidence which suggests that quadriceps weakness may precede the onset of radiographic evidence of OA and subsequent pain, and therefore may be directly involved in its pathogenesis. Furthermore, targeted exercise regimes aimed at improving quadriceps function indicate therapeutic benefits with regards to both the initiation and progression of knee OA. Quadriceps muscle dysfunction in knee OA is currently poorly understood and represents an unmet clinical need.

Consequently, the main aims of this work were to characterise quadriceps muscle dysfunction in the rodent meniscectomy-induced (MNX) and spontaneous guinea pig model of OA at the molecular level determining changes in muscle fibre type, metabolic potential, and muscle atrophy signalling. Furthermore, the effects of clenbuterol-induced quadriceps hypertrophy, prior to the induction of OA, on disease severity were considered in the rat MNX model. Thus far, the cDNA sequences encoding each member of the myosin heavy chain (MHC) gene family have yet to be determined in the guinea pig. Therefore, a further aim of this work was to generate novel cDNA sequence pertaining to the skeletal muscle-associated isoforms of MHC in the guinea pig, and to develop specific oligonucleotide primers to determine the abundance of each specific mRNA.

The development of MNX-induced and spontaneous OA was associated with changes in MHC I expression indicative of an increase in slow, type I muscle fibres. The assessment of muscle atrophy-associated genes revealed that neither model was associated with overt quadriceps muscle atrophy, or increased muscle atrophy signalling. Combined, these data suggest that OA associated quadriceps dysfunction may result predominantly from altered contractile properties, as evidenced by altered MHC expression, rather than from reduced quadriceps mass per se. The administration of clenbuterol for 14 days induced marked increases in quadriceps mass relative to bodyweight. However, clenbuterol induced hypertrophy was unable to favourably modulate OA severity in the MNX-induced model in this experimental setting.

In conclusion this work has shown that OA is associated with altered quadriceps muscle properties, suggestive of a switch towards a slow-twitch muscle fibre type, in two independent animal models. Such data have important implications for the development of targeted pharmaceuticals and in the prescription of rehabilitation regimes aimed at improving OA severity or reducing disease progression. Moreover, the relationship of increased MHC I expression to joint stability and muscle function warrants further investigation in the OA setting.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Parr, Tim
Jones, Simon
Bardsley, Ronald
Doherty, Michael
Maciewicz, Rose
Keywords: Skeletal muscle, MHC, myosin heavy chain, muscle, dysfunction, clenbuterol, atrophy, hypertrophy
Subjects: R Medicine > RC Internal medicine
Faculties/Schools: UK Campuses > Faculty of Science > School of Biosciences
Item ID: 11820
Depositing User: EP, Services
Date Deposited: 02 Dec 2011 17:12
Last Modified: 16 Dec 2017 15:44

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