Follistatin-like 3 is a mediator of exercise-driven bone formation and strengthening

Abstract

Exercise is vital for maintaining bone strength and architecture. Follistatin like 3 (FSTL3), a member of Follistatin family, is a mechanosensitive protein upregulated in response to exercise and is involved in regulating musculoskeletal health, we investigated the potential role of FSTL3 in exercise-driven bone remodeling. Exercise-dependent regulation of bone structure and functions was compared in mice with global Fstl3 gene deletion (Fstl3−/−) and their age-matched Fstl3+/+ littermates. Mice were exercised by low-intensity treadmill walking. The mechanical properties and mineralization were determined by μCT, three-point bending test and sequential incorporation of calcein and alizarin complexone. ELISA, Western-blot analysis and qRT-PCR were used to analyze the regulation of FSTL3 and associated molecules in the serum specimens and tissues. Daily exercise significantly increased circulating FSTL3 levels in mice, rats and humans. Compared to age-matched littermates, Fstl3−/− mice exhibited significantly lower fracture tolerance, having greater stiffness, but lower strain at fracture and yield energy. Furthermore, increased levels of circulating FSTL3 in young mice paralleled greater strain at fracture compared to the lower levels of FSTL3 in older mice. More significantly, Fstl3−/− mice exhibited loss of mechanosensitivity and irresponsiveness to exercise-dependent bone formation as compared to their Fstl3+/+ littermates. In addition, FSTL3 gene deletion resulted in loss of exercise-dependent sclerostin regulation in osteocytes and osteoblasts, as compared to Fstl3+/+ osteocytes and osteoblasts, in vivo and in vitro. The data identifies FSTL3 as a critical mediator of exercise-dependent bone formation and strengthening and point to its potential role in bone health and in musculoskeletal diseases.

Strength Training Session Induces Important Changes on Physiological, Immunological, and Inflammatory Biomarkers

“…Follistatin-like-1 (FLST1) is a cytokine with diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like-1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure [ 63 ]. Here, the basal levels of FLST1 between TG and UTG present a statistical difference ( Figure 4(d) ).…”

“…Here, the basal levels of FLST1 between TG and UTG present a statistical difference ( Figure 4(d) ). There is research showing that exercise can induce the elevation of FLST1 in circulation, depending on the type of exercise and the status of the group [ 63 ]. Here, the single strength training session elevated the plasma concentration of these molecules immediately after the end of exercise, but only in TG.…”

Mechanosensitive miRNAs and Bone Formation

“…Clinically, a lack of mechanical stimuli (e.g., aging, paralysis) or exposure to external mechanical unloading (e.g., during bed-rest or hind-limb unloading, or under the conditions experienced by astronauts) reduce weight-bearing bone formation and weaken bone structure [ 5 , 6 , 7 , 8 ]. Previous reports from our laboratory and others have demonstrated that multifactorial regulators are involved in the mechanical stimuli modulating the activity of osteogenic cells and bone formation, such as hormones or cytokine (e.g., parathyroid hormone [ 9 ], glucocorticoid [ 10 ], follistatin-like 3 [ 11 ]), cytoskeleton proteins (e.g., microtubule actin crosslinking factor 1 [ 12 ], connexin 43 [ 13 ]), signaling pathways (e.g., Wnt signaling [ 14 , 15 ]) and microRNAs (miRNAs).…”

A comparative study on normal and obese mice indicates that the secretome of mesenchymal stromal cells is influenced by tissue environment and physiopathological conditions

“…Ang (angiogenin), Pgf (placenta growth factor), and Angptl4 (angiopoietin-like 4) could be the key players in angiogenesis of the sWAT-MSC secretome, as evidenced in the Reactome analysis [ 28 – 30 ]. Fstl3 (follistatin) may be one the most important components of the sWAT-MSC secretome, since it conducts key functions in regulation of fat accumulation and insulin sensitivity, modulation of hematopoiesis, and control of bone formation [ 31 – 33 ]. The GCL, Prdx5, and Prdx6 proteins are part of the redox activity network.…”