UC Berkeley

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. These characteristics of aged muscle are also features of striated muscle diseases including Duchenne muscular dystrophy (DMD) and myocardial infarction (MI). Here, we identify the microRNA miR-128-3p as a post-transcriptional regulator that links mitochondrial dysfunction and chronic inflammation across aging and disease. Genetic variation at the miR-128-1 locus associates with grip strength and pulmonary function in humans, supporting a role in muscle aging. Subcutaneous delivery of a locked nucleic acid antisense oligonucleotide targeting miR-128-3p (anti-miR-128) restores muscle mass and function in aged mice, preserves cardiac function and limits adverse remodeling following MI, and ameliorates pathology in mouse and porcine models of DMD. Notably, anti-miR-128 confers benefit even when delivered two hours post-MI. Across contexts, anti-miR-128 activates mitochondrial programs while suppressing inflammatory signaling, recapitulating the transcriptional signature of caloric restriction, rapamycin, heterochronic parabiosis, and other longevity interventions, and is well tolerated with chronic dosing in mice and non-human primates. Together, these findings raise the possibility that acute, chronic, and degenerative striated muscle diseases can be viewed along a continuum of sustained muscle injury converging on a conserved aging-associated program and establish miR-128-3p inhibition as a druggable target capable of restoring function along this continuum.