A positively selected microRNA controls a reversible aging program in striated muscle

Boldridge, M. A., Xu, L., Wang, X., Stirm, M., Bonilla, G., Zhu, C., Lee, J. Y., Stark, R. L., Damal Villivalam, S., Bengtson Loevendorf, M., Petri, A., Wagschal, A., Gilroy, C., Gonzalez, F., Cai, L., Hecker, P. I., Vyberg, M., Almeida, R., Punnati, C., Jin, C., Schnurr, T. M., Riddell, D. O., Hildyard, J. C. W., Shashikadze, B., Lange, A., Klymiuk, N., Froehlich, T., Kauppinen, S., Piercy, R. J., Knowles, J. W., Fay, A., Kang, S., Temel, R. E., Sadreyev, R. I., Wolf, E., Springer, M. L., Naar, A. M.

Department of Metabolic Biology and Nutrition, University of California, Berkeley, California, USADepartment of Metabolic Biology and Nutrition, University of California, Berkeley, California, USA · biorxiv

Paper

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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Research summary

Inhibition of miR-128-3p via antisense oligonucleotides restores muscle mass and function in aged mice and improves cardiac outcomes by activating mitochondrial programs and suppressing inflammation. This paper is highly relevant because it identifies a specific, positively selected genetic target that modulates a conserved aging-associated transcriptional program, offering a potential mechanism to reverse age-related functional decline rather than merely treating symptoms.

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