A positively selected microRNA controls a reversible aging program in striated muscle
- 1Department of Metabolic Biology and Nutrition, University of California, Berkeley, California, USA
Abstract
Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.
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BibTeX
@misc{boldridge2026positively,
title = {{A positively selected microRNA controls a reversible aging program in striated muscle}},
author = {M. A. Boldridge and L. Xu and X. Wang and M. Stirm and G. Bonilla and C. Zhu and J. Y. Lee and R. L. Stark and S. Damal Villivalam and M. Bengtson Loevendorf and A. Petri and A. Wagschal and C. Gilroy and F. Gonzalez and L. Cai and P. I. Hecker and M. Vyberg and R. Almeida and C. Punnati and C. Jin and T. M. Schnurr and D. O. Riddell and J. C. W. Hildyard and B. Shashikadze and A. Lange and N. Klymiuk and T. Froehlich and S. Kauppinen and R. J. Piercy and J. W. Knowles and A. Fay and S. Kang and R. E. Temel and R. I. Sadreyev and E. Wolf and M. L. Springer and A. M. Naar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749250},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749250v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A positively selected microRNA controls a reversible aging program in striated muscle
AU - M. A. Boldridge
AU - L. Xu
AU - X. Wang
AU - M. Stirm
AU - G. Bonilla
AU - C. Zhu
AU - J. Y. Lee
AU - R. L. Stark
AU - S. Damal Villivalam
AU - M. Bengtson Loevendorf
AU - A. Petri
AU - A. Wagschal
AU - C. Gilroy
AU - F. Gonzalez
AU - L. Cai
AU - P. I. Hecker
AU - M. Vyberg
AU - R. Almeida
AU - C. Punnati
AU - C. Jin
AU - T. M. Schnurr
AU - D. O. Riddell
AU - J. C. W. Hildyard
AU - B. Shashikadze
AU - A. Lange
AU - N. Klymiuk
AU - T. Froehlich
AU - S. Kauppinen
AU - R. J. Piercy
AU - J. W. Knowles
AU - A. Fay
AU - S. Kang
AU - R. E. Temel
AU - R. I. Sadreyev
AU - E. Wolf
AU - M. L. Springer
AU - A. M. Naar
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749250
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749250v1
AB - Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.
ER -