Previously, using a forward genetic approach we identified B. burgdorferi arthritis-associated locus 1 (Bbaa1), a quantitative trait locus on Chr4, which physically encompasses the type I IFN gene cluster and regulates Lyme arthritis through heightened type I IFN production. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the Bbaa1 interval, and RNA-seq of resident CD45- joint cells from advanced interval specific recombinant congenic lines (ISRCL4 and ISRCL3) identified myostatin as uniquely upregulated in association with Bbaa1 arthritis development. Our manuscript further demonstrates that myostatin expression is linked to IFN-ÃŸ production, and in vivo inhibition of myostatin suppresses Lyme arthritis in the reduced interval Bbaa1 congenic mice, formally implicating myostatin as a novel downstream mediator of joint-specific inflammatory response to B. burgdorferi. Overall design: 22 days following infection with B. burgdorferi, mouse rear ankle joints were gently digested into single-cell suspensions and CD45 negative cells were isolated by magnetic bead separation. CD45 negative cells from both rear ankle joints of two mice were pooled for each n sample in order to increase RNA concentration for gene expression analysis (n=5 per genotype). Gene expression comparisons were made between B6 (control group) and ISRCL4/ISRCL3 congenic lines.