Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

Abstract

Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified.

Keywords: Anti-cytokines; Atrophy; Cachexia; Celecoxib (PubChem CID: 2662); Cis-resveratrol (PubChem CID: 1548910); Clenbuterol (PubChem CID: 2783); Cox2 inhibitor; EPA (PubChem CID: 446284); Eicosapentaenoic acid; Enobosarm (PubChem CID: 11326715); Formoterol (PubChem CID: 3410); Ghrelin (PubChem CID: 44576256); Histone decetylase inhibitor; Megestrol acetate; Megestrol acetate (PubChem CID: 11683); Meloxicam (PubChem CID: 54677470); Pentoxifylline (PubChem CID: 4740); Phosphodiesterase inhibitor; Resveratrol; Thalidomide (PubChem CID: 5426); Torbafylline (PubChem CID: 65888); Trans-resveratrol (PubChem CID: 445154); Trichostatin A (PubChem CID: 444732); β-Adrenoceptor agonists; β-Hydroxy-β-methylbutyrate (PubChem CID: 69362).