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Differential response of tissue engineered skeletal muscle from rheumatoid arthritis patients and healthy controls

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease, causing pain, increased mortality, and profound disability rates. RA affects articular joints and multiple organs, including skeletal muscle. Loss of muscle mass is associated with increased disability in RA. We developed an in vitro tissue-engineered human skeletal muscle model (myobundle) to better understand the disease mechanisms driving muscle loss in RA. Myobundles were generated using primary skeletal muscle cells from the vastus lateralis muscle of 5 RA patients and 4 age-matched healthy controls. Compared to controls, RA myobundles were more sensitive to IFN-γ, leading to reduced contractile force. Gene sets enriched in IFN-γ-treated RA myobundles, but not IFN-γ-treated controls, were involved in the response to hypoxia and the unfolded protein response. We identified PIM1 as a selectively upregulated gene and verified altered protein expression by Western blotting. Tofacitinib restored contractile force and myosin heavy chain protein levels in RA myobundles with IFN-γ-induced dysfunction. Thus, human myobundles can model inflammation of muscle in RA and other diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283881 | GEO | 2025/03/19

REPOSITORIES: GEO

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Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation. We used microarrays to gain insight into potential mechanisms of DS-associated skeletal muscle weakness. Soleus muscles were obtained from four male Ts65Dn (DS) mice and four male colony control mice. Animals were apparently healthy and approximately five months old. The muscles were harvested in the basal state under anesthesia induced by sodium pentobarbital at approximately the same time of the day.

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Differential response of tissue engineered skeletal muscle from rheumatoid arthritis patients and healthy controls

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