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[Preprint]. 2025 Jan 21:2024.03.28.586997. Originally published 2024 Mar 31. [Version 2] doi: 10.1101/2024.03.28.586997

Figure 3 – Foxc1 and Arid5a directly regulate muscle insulin sensitivity and lipotoxicity.

Figure 3 –

(A) Muscle-wide transduction by the MyoAAV-serotyped vectors. (B-C) In WT mice on normal diet, Foxc1 overexpression is sufficient to upregulate Insr and Irs1, and increase insulin-driven 2DG uptake in muscle. (D-F) In WT mice on normal diet, Arid5a overexpression is sufficient to lower Cd36, Fabp4 and triacylglycerol (TG) levels in muscle. (G) Co-transduction of MyoAAV-Foxc1 and -Arid5a reduces the effects of diet-induced obesity on glycemia, muscle glucose uptake and muscle TG content, while recapitulating each of the target gene effects for either Foxc1 or Arid5a. (H) Foxc1 and Arid5a gene programs in muscle are upregulated by the insulin-sensitizing once-weekly prednisone treatment, while downregulated by the insulin-desensitizing once-daily prednisone treatment. (I-J) MyoAAV-driven knockdown in muscle in high-fat diet conditions showed Foxc1 requirement for Insr, Irs1 expression and muscle 2DG uptake, and Arid5a requirement for Cd36, Fabp4 repression and muscle TG lowering. n=3–5♂/group; diet exposures for 12 weeks from 4mo to 7mo; Welch’s t-tests and 1w ANOVA + Sidak (H): ns, non significant; *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001.