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The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy.

ABSTRACT: It is generally believed that muscle weakness in patients with polymyositis and dermatomyositis is due to autoimmune and inflammatory processes. However, it has been observed that there is a poor correlation between the suppression of inflammation and a recovery of muscle function in these patients. This study was undertaken to examine whether nonimmune mechanisms also contribute to muscle weakness. In particular, it has been suggested that an acquired deficiency of AMP deaminase 1 (AMPD1) may be responsible for muscle weakness in myositis.We performed comprehensive functional, behavioral, histologic, molecular, enzymatic, and metabolic assessments before and after the onset of inflammation in a class I major histocompatibility complex (MHC)-transgenic mouse model of autoimmune inflammatory myositis.Muscle weakness and metabolic disturbances were detectable in the mice prior to the appearance of infiltrating mononuclear cells. Force contraction analysis of muscle function revealed that weakness was correlated with AMPD1 expression and was myositis specific. Decreasing AMPD1 expression resulted in decreased muscle strength in healthy mice. Fiber typing suggested that fast-twitch muscles were converted to slow-twitch muscles as myositis progressed, and microarray results indicated that AMPD1 and other purine nucleotide pathway genes were suppressed, along with genes essential to glycolysis.These data suggest that an AMPD1 deficiency is acquired prior to overt muscle inflammation and is responsible, at least in part, for the muscle weakness that occurs in the mouse model of myositis. AMPD1 is therefore a potential therapeutic target in myositis.

SUBMITTER: Coley W

PROVIDER: S-EPMC3485437 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy.

Coley William W Rayavarapu Sree S Pandey Gouri S GS Sabina Richard L RL Van der Meulen Jack H JH Ampong Beryl B Wortmann Robert L RL Rawat Rashmi R Nagaraju Kanneboyina K

Arthritis and rheumatism 20121101 11

<h4>Objective</h4>It is generally believed that muscle weakness in patients with polymyositis and dermatomyositis is due to autoimmune and inflammatory processes. However, it has been observed that there is a poor correlation between the suppression of inflammation and a recovery of muscle function in these patients. This study was undertaken to examine whether nonimmune mechanisms also contribute to muscle weakness. In particular, it has been suggested that an acquired deficiency of AMP deamina ...[more]

PMID: 22806328

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Project description:BackgroundMuscle weakness is a common symptom in numerous diseases and a regularly occurring problem associated with ageing. Prolonged low-frequency force depression (PLFFD) is a form of exercise-induced skeletal muscle weakness observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca2+ release, decreased myofibrillar Ca2+ sensitivity, and myofibrillar dysfunction. We here used these three forms of PLFFD as models to study the effectiveness of a fast skeletal muscle troponin activator, CK-2066260, to mitigate muscle weakness.MethodsExperiments were performed on intact single muscle fibres or fibre bundles from mouse flexor digitorum brevis, which were stimulated with electrical current pulses, while force and the free cytosolic [Ca2+ ] ([Ca2+ ]i ) were measured. PLFFD was induced by three different stimulation protocols: (i) repeated isometric contractions at low intensity (350 ms tetani given every 5 s for 100 contractions); (ii) repeated isometric contractions at high intensity (250 ms tetani given every 0.5 s for 300 contractions); and (iii) repeated eccentric contractions (350 ms tetani with 20% length increase given every 20 s for 10 contractions). The extent and cause of PLFFD were assessed by comparing the force-[Ca2+ ]i relationship at low (30 Hz) and high (120 Hz) stimulation frequencies before (control) and 30 min after induction of PLFFD, and after an additional 5 min of rest in the presence of CK-2066260 (10 μM).ResultsProlonged low-frequency force depression following low-intensity and high-intensity fatiguing contractions was predominantly due to decreased sarcoplasmic reticulum Ca2+ release and decreased myofibrillar Ca2+ sensitivity, respectively. CK-2066260 exposure resulted in marked increases in 30 Hz force from 52 ± 16% to 151 ± 13% and from 6 ± 4% to 98 ± 40% of controls with low-intensity and high-intensity contractions, respectively. Following repeated eccentric contractions, PLFFD was mainly due to myofibrillar dysfunction, and it was not fully reversed by CK-2066260 with 30 Hz force increasing from 48 ± 8% to 76 ± 6% of the control.ConclusionsThe fast skeletal muscle troponin activator CK-2066260 effectively mitigates muscle weakness, especially when it is caused by impaired activation of the myofibrillar contractile machinery due to either decreased sarcoplasmic reticulum Ca2+ release or reduced myofibrillar Ca2+ sensitivity.

Dataset Information

The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy.

Publications

The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy.

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