Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury

Sharma, B.; Rehman, H.; Lu, X.; Figueiredo, V. C.; Van Remmen, H.; Kuang, S.; Brooks, S. V.; Davis, C.; Maddipati, K. R.; Markworth, J. F.

doi:10.1101/2025.05.13.653766

bioRxiv · 10.1101/2025.05.13.653766

Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury

Sharma, B.·Rehman, H.·Lu, X.·Figueiredo, V. C.·Van Remmen, H.·Kuang, S.·Brooks, S. V.·Davis, C.·Maddipati, K. R.·Markworth, J. F.

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Abstract

Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) can promote timely resolution of inflammation while stimulating skeletal muscle regeneration. Despite this, the potential role of endogenous inflammation-resolution circuits in skeletal muscle injury and repair remains unknown. Here, we investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration following skeletal muscle injury in mice. Prior to muscle injury, Alox15-/- mice displayed lower intramuscular concentrations of 12/15-LOX-derived lipid mediators than wild type (WT) mice, and this was associated with chronic low-grade muscle inflammation. Alox15-/- mice mounted an exaggerated acute immune response to sterile skeletal muscle injury which was associated with a local imbalance of pro-inflammatory vs. pro-resolving lipid mediators. During the regenerative phase, Alox15-/- mice displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (M[FE]) obtained from Alox15-/- mice produced less 12/15-LOX-derived lipid mediators and this was associated with impaired M2 polarization. Isolated myogenic progenitor cells also produced many LOX metabolites in response to long chain polyunsaturated fatty acid (LC-PUFA) supplementation, including bioactive SPMs. Alox15-/- myoblasts were both impaired in their ability to produce SPMs and were insensitive to the stimulatory effect of LC-PUFAs on in vitro myogenesis. These data show that the 12/15-LOX pathway is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.

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Sharma, B., Rehman, H., Lu, X., Figueiredo, V. C., Van Remmen, H., Kuang, S., Brooks, S. V., Davis, C., Maddipati, K. R., Markworth, J. F.. 2025-05-17. Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury. https://doi.org/10.1101/2025.05.13.653766

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