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BACKGROUND: Muscle weakness is a common comorbidity in rheumatoid arthritis (RA), resulting in long-term disability, reduced work productivity, and quality of life in RA patients. Although underlying mechanisms are not completely understood, emerging data from Lanner´s group suggest that mitochondrial dysfunction and oxidative stress are implicated in RA-induced muscle weakness.

AIM: To examine a possible correlation between muscle weakness, mitochondrial dysfunction, and altered calcium handling in complete Freund's adjuvant (CFA)-induced RA mouse model and whether mitochondrial alterations could be rescued by PGC-1α1 overexpression, a master regulator of mitochondrial biogenesis.

METHODS: RA and associated muscle weakness was induced in two months old female C57BL/6JRjand PGC-1α1 muscle-specific transgenic mice by intra-articular injection of CFA. In response to two electrical stimulation protocols, cytoplasmic and mitochondrial Ca²⁺ levels and changes in mitochondrial membrane potential (ΔΨ) were measured in FDB muscle fibres using live cell imaging. Mitochondrial respirometry and immunoblotting were performed to evaluate mitochondrial function and protein expression.

RESULTS: Fatigue stimulation revealed no significant differences in mitochondrial Ca²⁺ levels ([Ca²⁺]_mit)between the groups. However, reduced lower [Ca²⁺]_mit and ΔΨ were observed during recovery in WT-CFA than in WT-SAL. Mitochondrial dysfunction was observed with decreased complex I and II activity, as well as reduced expression of ETC-related subunits. PGC-1α1 overexpression was able to ameliorate the impaired calcium uptake during recovery and decreased ETC subunit expression caused by CFA.

CONCLUSION: Muscle dysfunction might be associated with mitochondrial dysfunction and altered Ca²⁺ handling and PGC-1α1 overexpression appears to rescue some of the alterations.