miR-128-3p Inhibition Improves Muscle Mass and Function in Aged Mice
That the calorie restriction imposed by GLP-1 receptor agonists induces loss of muscle mass has proved a boon for research into ways to address the loss of muscle mass that occurs with age, contributing to frailty. Suddenly a relatively large amount of funding and industry attention is available for programs that might result in a drug to prevent muscle loss in GLP-1 receptor agonist patients, and most of those options can at least in principle be used to treat age-related muscle loss. Here, researchers demonstrate a novel approach to inducing muscle growth in aged mice, by inhibiting a relevant microRNA; the technology is developed by Elenae Therapeutics which, as is usual, targets more severe and less common indications at the outset, such as improving outcomes for heart muscle following a heart attack. Given an approved drug at some point in the future, then it becomes possible to discuss other applications.
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.