Protective effects of 3-(4-hydroxy-3-methoxyphenyl) propionic acid against dexamethasone-induced muscle atrophy: modulation of associated genes and oxidative stress in female mice

Muscle atrophy is a growing concern, particularly in older adults and people with sedentary lifestyles. Because treatment options are limited, extensive research is crucial to discover novel therapeutic agents. Thus, we investigated the effect of 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) and its parent compound, 4-hydroxy-3-methoxycinnamic acid (HMCA), on dexamethasone (Dex)-induced muscle atrophy in C57BL/6J female mice. Dex injection (10 mg/kg body weight [BW] in mice for 10 consecutive days negatively affected body weight, gastrocnemius and tibialis anterior muscle mass, myofiber cross sectional area (CSA) and level of myosin heavy chain (MyHC) protein. Atrogin-1 and muscle ring finger protein-1, two major muscle atrophy-associated ubiquitin ligases, were significantly increased following Dex administration, along with their upstream regulators forkhead box O3a (FoxO3a) and Krüppel-like factor 15 (KLF15). Furthermore, Dex-induced oxidative stress by increasing malondialdehyde and advanced oxidation protein products in plasma and skeletal muscle. Intriguingly, HMPA and HMCA administration (50 mg/kg BW) for 21 days effectively prevented the attenuation of muscle mass, myofiber CSA and MyHC protein levels and suppressed ubiquitin ligase expression by ameliorating the upstream transcriptional factors FoxO3a and KLF15. Moreover, increased oxidative stress and oxidative stress-sensitive casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) ubiquitin ligase induced by Dex were effectively diminished by HMPA/HMCA administration. These observations suggest that HMPA and HMCA may be potential <i>in vivo</i> therapeutic agents that attenuate muscle atrophy by reversing atrophy-mimicking genes, oxidative stress, and related anomalies.