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Postpartum (PP) maternal mortality remains alarmingly high, with a rate of 32.9 per 100,000 live births in 2021 in the United States. Cardiovascular diseases, including peripartum/postpartum cardiomyopathy (PPCM) and coronary heart disease, are among the leading causes of PP morbidity and mortality. Although socioeconomic status and the level of PP care can influence the mortality rate, the underlying mechanisms leading to PPCM are not well understood. PPCM is clinically defined as (1) the development of the disease in the last month of pregnancy or within 5 months of delivery, (2) absence of pre-existing heart disease prior to the last month of pregnancy, (3) unknown cause of heart failure, and (4) left ventricular systolic dysfunction. Prognosis remains poor, with full recovery reported in only 23% of affected individuals and 50% experiencing heart failure-related mortality due to limited therapeutic options. Limited studies in both humans and mouse models of PPCM have proposed several potential mechanisms, including inflammation, viral myocarditis, autoimmune reactions, oxidative stress, and apoptosis, resulting from environmental as well as genetic factors. Studying these mechanisms in animal models, particularly those involving genetic causes, has been difficult due to the lack of severity or relevance of existing mouse models of PPCM to the human disease.

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

Binayok Sharma, Xinyue Lu, Hamood Rehman, Vandré C. Figueiredo, ... James F. Markworth

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

 

Objectives

Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) promotes 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.

Methods

We investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration in vivo following skeletal muscle injury in mice. We further tested the impact of 12/15-LOX deficiency on polarization of bone marrow-derived macrophages and differentiation of myogenic progenitor cells in vitro.

Results

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. Alox15−/− mice also displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (MФ) 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.

Conclusions

12/15-LOX is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.

 

 

Articles in Press

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

Binayok Sharma, Xinyue Lu, Hamood Rehman, Vandré C. Figueiredo, ... James F. Markworth

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

 

Objectives

Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) promotes 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.

Methods

We investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration in vivo following skeletal muscle injury in mice. We further tested the impact of 12/15-LOX deficiency on polarization of bone marrow-derived macrophages and differentiation of myogenic progenitor cells in vitro.

Results

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. Alox15−/− mice also displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (MФ) 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.

Conclusions

12/15-LOX is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.

 

 

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13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

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