Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling

David E. Lee, Lauren K. McKay, Akshay Bareja, Yongwu Li, Alastair Khodabukus, Nenad Bursac, Gregory A. Taylor, Gurpreet S. Baht and James P. White ()
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David E. Lee: Duke University School of Medicine
Lauren K. McKay: Duke University School of Medicine
Akshay Bareja: Duke University School of Medicine
Yongwu Li: Duke University
Alastair Khodabukus: Duke University
Nenad Bursac: Duke University
Gregory A. Taylor: VA Health Care System
Gurpreet S. Baht: Duke University School of Medicine
James P. White: Duke University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Pathologies associated with sarcopenia include decline in muscular strength, lean mass and regenerative capacity. Despite the substantial impact on quality of life, no pharmacological therapeutics are available to counteract the age-associated decline in functional capacity and/or, resilience. Evidence suggests immune-secreted cytokines can improve muscle regeneration, a strategy which we leverage in this study by rescuing the age-related deficiency in Meteorin-like through several in vivo add-back models. Notably, the intramuscular, peptide injection of recombinant METRNL was sufficient to improve muscle regeneration in aging. Using ex vivo media exchange and in vivo TNF inhibition, we demonstrate a mechanism of METRNL action during regeneration, showing it counteracts a pro-fibrotic gene program by triggering TNFα-induced apoptosis of fibro/adipogenic progenitor cells. These findings demonstrate therapeutic applications for METRNL to improve aged muscle, and show Fibro/Adipogenic Progenitors are viable therapeutic targets to counteract age-related loss in muscle resilience.

Date: 2022
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DOI: 10.1038/s41467-022-35390-3

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