Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans

Abstract

Sarcopenia, characterized by age-related loss of muscle mass, strength, and decreased physical performance, is a growing public health challenge amid the rapidly ageing population. As there are no approved drugs that target sarcopenia, it has become increasingly urgent to identify promising pharmacological interventions. In this study, we conducted an integrative drug repurposing analysis utilizing three distinct approaches. Firstly, we analyzed skeletal muscle transcriptomic sequencing data in humans and mice using gene differential expression analysis, weighted gene co-expression analysis, and gene set enrichment analysis. Subsequently, we employed gene expression profile similarity assessment, hub gene expression reversal, and disease-related pathway enrichment to identify and repurpose candidate drugs, followed by the integration of findings with rank aggregation algorithms. Vorinostat, the top-ranking drug, was also validated in an in vitro study, which demonstrated its efficacy in promoting muscle fiber formation. Although still requiring further validation in animal models and human clinical trials, these results suggest a promising drug repurposing prospect in the treatment and prevention of sarcopenia.

Age Is Just a Number: Progress and Obstacles in the Discovery of New Candidate Drugs for Sarcopenia

“…The potential of vorinostat to treat sarcopenia was assessed in murine C2C12 myotubes. Vorinostat increased myotube differentiation, diameter, and MHC levels [180].…”

“…Computational-based methodologies have been applied to drug repositioning for sarcopenia. A recent example was provided by Liang et al based on the analysis of skeletal muscle transcriptomic sequencing data in humans and mice to obtain the Gene Signature of Sarcopenia, coupled with literature validation [180]. This led to the identification of vorinostat (brand name zolinza, a histone deacetylase inhibitor used to treat cutaneous T cell lymphoma [181]) as the top-ranking drug.…”

Emerging Therapeutic Strategies in Sarcopenia: An Updated Review on Pathogenesis and Treatment Advances

“…As ongoing research reveals sarcopenia's intricate molecular mechanisms and therapeutic targets, it becomes clear that novel treatments must be urgently developed. In particular, the lack of clinically-approved pharmaceuticals for this illness intensifies the need for identifying/establishing new drug formulations and diversifying treatment approaches [22,[54][55][56]. Taking into account the research directions recognized in recent literature, the following subsections describe the potential of several emerging therapeutic formulations, drug delivery systems, stem cell therapies, and tissue-engineered scaffolds.…”

“…Despite the few new therapeutic possibilities, drug discovery and development are costly and time-consuming, with a low success approval rate for emerging formulations and the necessity for numerous testing stages before clinical implementation. Thus, as an alternative, drug repurposing has been gathering more attention in recent years toward maximizing the effects of pharmacotherapies for sarcopenia [23,55]. Drugs that are currently used for other diseases may be explored in sarcopenia based on their pro-anabolic or anti-inflammatory properties that translate to improvements in skeletal muscle mass and function [23].…”