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The Role of Irisin in Initiating Resorption During the Skeletal Response to Exercise

Award Number: K01AR081959
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The Role of Irisin in Initiating Resorption During the Skeletal Response to Exercise - Irisin is a novel signaling peptide proteolyzed from the cell membrane-bound protein Fndc5 (fibronectin type III domain-containing protein 5), first described by our collaborators to release from muscle during exercise and induce a thermogenic program in beige adipose tissue. A growing body of work has highlighted another key role for irisin in mediating the effect of exercise on bone. Early work described an anabolic action, with intermittent low doses of irisin stimulating cortical bone formation and preventing unloading-induced bone loss in vivo, and serum-derived irisin from exercised mice enhancing osteoblastogenesis in vitro. Our group has employed a genetic approach to further elucidate the role of irisin in skeletal remodeling, demonstrating that forced expression of Fndc5 in muscle markedly reduced bone formation and osteoblast numbers while increasing sclerostin (SOST) expression and osteoclast numbers. Global genetic deletion of Fndc5 conferred complete protection against ovariectomy-induced bone loss, marked by maintenance of osteocyte lacunae and blocked bone resorption with no increases in Receptor Activator of Nuclear Factor Kappa-β Ligand (RANKL) expression despite prolonged estrogen deprivation. Similarly, short term irisin infusions in wild type mice resulted in higher serum levels of sclerostin and RANKL. These results highlight the breadth of irisin’s signaling effects in bone, and the need to further understand its overall impact on resorption and remodelling. We now have additional evidence that irisin signals directly to the osteoclast via integrin αVβ5, stimulating differentiation and resorption. The present work endeavors to delineate the full signaling pathway in the osteoclast, while employing novel in vivo models to test this regulation of resorption in the context of skeletal response to exercise. We have developed a novel conditional mouse allele of Fndc5 and generated a skeletal muscle- specific targeted null, which we will use to test the effect of muscle-derived irisin on bone response to exercise. In parallel, we will utilize in vitro techniques to confirm the putative receptors for irisin and characterize intracellular signal transduction in the osteoclast. To comprehensively assess irisin’s impact on bone resorption, we will also investigate indirect effects of irisin on the osteoclast, through regulation by the osteocyte. Finally, as osteocyte response to mechanical cues is a key aspect of this cell’s function during exercise, we will investigate the potential interplay between irisin signaling and mechanosensitivity. We predict pleiotropic effects of irisin – it may be a coupling factor by directly stimulating both the osteoblast and osteoclast, and also serve a unique role as a counter regulatory hormone to maintain calcium homeostasis by increasing resorption. By focusing on the osteoclast, this work seeks to elucidate irisin’s role in initiating bone resorption and better understand its influence on remodeling as a whole. Such insights both provide a greater understanding of skeletal response to exercise but inform efforts to address bone degenerative diseases by taking advantage of native signaling pathways.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $126,900 )
2026	2026	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/28/2026	NON-COMPETING CONTINUATION	$126,900
														Subtotal = $126,900

Issue Date FY: 2025 ( Subtotal = $126,900 )
2025	2025	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	3/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$126,900
2025	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/13/2025	NON-COMPETING CONTINUATION	$0
2025	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	5/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $126,900

Issue Date FY: 2024 ( Subtotal = $127,427 )
2024	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/27/2024	NON-COMPETING CONTINUATION	$127,427
														Subtotal = $127,427

Issue Date FY: 2023 ( Subtotal = $127,427 )
2023	2023	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/1/2023	NEW	$127,427
														Subtotal = $127,427

Grand Total All Awards = $508,654

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The Role of Irisin in Initiating Resorption During the Skeletal Response to Exercise

Award Number: K01AR081959

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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