Impact of mechanical unloading on the irisin precursor, FNDC5, in skeletal muscle of sheep as a large animal experimental model.

Scientific evidence has demonstrated the involvement of irisin, a molecule produced by muscle contraction, in preventing the onset of musculoskeletal decline. We previously demonstrated that the expression of irisin and its muscle-derived precursor FNDC5 is affected by unloading in skeletal muscle of hindlimb-unloaded (HU) mice. Studies in the HU mouse model showed that treatment with irisin prevents muscle wasting and atrophy. In parallel, human studies documented a strong association between irisin/FNDC5 and muscle function. Therefore, the scientific community is committed to determining whether irisin may represent a promising clinical strategy for preventing and treating disorders caused by muscle inactivity, such as those affecting bedridden or elderly patients. In translational research from mice to humans, there are very few in vivo studies conducted on large animals. The sheep model is an excellent model for studying the musculoskeletal system due to its anatomical characteristics, which share similarities with humans, allowing for the reproduction of mechanical load distribution on the limbs. To provide translational knowledge on the progression of muscle atrophy, we evaluated the impact of unloading on the expression of FNDC5 and functional proteins of skeletal muscle in sheep. Our findings revealed a reduction of FNDC5 in the quadriceps muscle after 2 wk of immobilization. The FNDC5 decrease is accompanied by a reduction of myosin isoforms