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

Abstract

OBJECTIVE 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 patients. We have therefore hypothesized that non-immune mechanisms also contribute to muscle weakness. In particular, it has been suggested that an acquired deficiency of AMP deaminase (AMPD1) may be responsible for muscle weakness in myositis. METHODS We have used comprehensive functional, behavioral, histological, molecular, enzymatic and metabolic assessments before and after the onset of inflammation in MHC class I mouse model of autoimmune inflammatory myositis. RESULTS We found that 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 AMDP1 expression and was myositis-specific. We also demonstrated that decreasing AMPD1 expression results in decreased muscle strength in healthy mice. Fiber typing suggested that fast-twitch muscles are converted to slow-twitch muscles as myositis progresses, and microarray results indicated that AMPD1 and other purine nucleotide pathway genes are suppressed, along with genes essential to glycolysis. CONCLUSION 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.

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

“…Here, I also observed similar trends in the force of hind-limb grip force, with lama4 weakened grip force suggests a non-progressive defect, which is in agreement with the coordination and body balance studies previously conducted by (Patton et al, 2001). Weaker grip force could result from alterations in fibre type compositions involving increased proportion of slow fibre types (Type I) with downregulation of fast fibre types (Coley et al, 2012;Lamboley et al, 2015). In order to determine this, I looked at fibre type expression in gastrocnemius muscles at 3MO and aged mice.…”

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies – potential role of ER stress pathways

“…This uncoupling of the ETC would result in a reduced ATP synthesis rate, creating an energy deficit, which again may contribute to muscle dysfunction [36]. Such a hypothesis is supported by recent in-vivo studies in the H2-k b murine model of myositis that has shown metabolic disturbances, whereby a deficiency in the enzyme AMP deaminase 1 (AMPD1) depresses muscle Adenosine diphosphate (ADP) and AMP levels, thus, causing muscle weakness derived from a bioenergetic imbalance [9]. Moreover, mitochondrial abnormalities have been described in IBM, which correlated with severity of disease [37 & ].…”

“…Specifically, many patients with apparently treatment-responsive disease, that is, little or no radiographic evidence for myoedema or histological evidence for T-cell infiltrations, remain weak and sometimes profoundly so, even without evidence of muscle damage [8]. Moreover, it has been shown that weakness may precede inflammatory cell infiltrations, for example, in an established murine model of IIM [9]. It thus appears that nonimmune cell-mediated mechanisms may play an important role in the induction of muscle weakness in IIM [10,11].…”

AMPD3 is associated with the malignant characteristics of gastrointestinal stromal tumors

“…AMPD1 is exclusively expressed in skeletal muscle, whereas AMPD2 and AMPD3 are ubiquitously expressed. Deficiencies in all three AMPDs have been reported in humans (7), and mutations in AMPD1 were associated with muscle weakness or pain in certain patients (10,11). AMPD2 deficiency is associated with pontocerebellar hypoplasia, which is a rare inherited and progressive neurodegenerative disorder (12).…”