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

## TL;DR

Factor VIII deficiency in mice causes bone issues and muscle changes, but FVIII treatment can restore bone health, though not all muscle effects are reversed.

## Contribution

First comprehensive characterization of musculoskeletal effects in FVIII knockout mice and the impact of FVIII supplementation.

## Key findings

- FVIII deficiency leads to osteoporotic bone changes and reduced vascularization in mice.
- FVIII treatment reverses bone abnormalities but not all muscle fiber type changes.
- Muscle proteomic and metabolomic differences were observed and partially corrected by FVIII.

## 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.