Factor VIII restores bone parameters and modulates muscle proteo-metabolome in Factor VIII knockout male mice.

Abstract

In addition to its role in hemostasis, Factor VIII (FVIII) has recently been shown to potentially impact angiogenesis, inflammation, osteopenia, and sarcopenia. This was explored here by studying the musculoskeletal development of FVIII knockout (FVIII^-/-) male mice. These animals developed an osteoporotic phenotype with significant bone microarchitectural alteration, reduced vascularization, and a lower osteoblastic population. Proteomic analyses revealed differentiating bone metabolism-related proteins between FVIII^-/- and wildtype mice. Weekly infusions of recombinant FVIII protein reversed this phenotype. Surprisingly, younger FVIII^-/- mice had heavier muscles with larger fibers, shifted from type IIx to type IIb, not reversed by FVIII treatment. Significant proteomic and metabolomic differences between wildtype and FVIII^-/- muscles were observed, some of which were reduced by FVIII treatment. This study provides the first comprehensive full-phenotypic characterization of bones and muscles in FVIII^-/- mice and demonstrates the benefits of FVIII supplementation to normalize their musculoskeletal phenotype.