Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action. (September 2015)

• Record Type: Journal Article
• Authors: Dutt, Vikas; Gupta, Sanjeev; Dabur, Rajesh; Injeti, Elisha; Mittal, Ashwani
• Is Part Of: Pharmacological research. Volume 99(2015:Sep.)
• Page Start: 86
• Page End: 100
• Publication Date: 2015-09
• Subjects: Cox cyclooxygenase -- CREB cAMP response element binding protein -- CACS cancer-related anorexia and cachexia syndrome -- CRP C-reactive protein -- COPD chronic obstructive pulmonary disease -- DAG des-acyl ghrelin -- ERK extracellular signal-regulated kinase -- EPA eicosapentaenoic acid -- FoxO forkhead box O -- Epac exchange protein directly activated by cAMP -- eIF4G and eIF4E eukaryotic translation initiation factor 4G and 4E -- HAT histone acetyltransferase -- HDAC histone deacetylase -- HETE hydroxyeicosatetraenoic acid -- HMB β-hydroxy-β-methylbutyrate -- LLC Lewis lung carcinoma -- MAC murine adeno-carcinoma -- NY neuropeptide Y -- NFκB nuclear factor kappa B -- PUFA polyunsaturated fatty acid -- PIF proteolysis-inducing factor -- PPARγ peroxisome proliferator-activated receptor -- PGE prostaglandin -- PDE phosphodiesterase -- PKA protein kinase A -- PTX pentoxifylline -- ROS reactive oxygen species -- STAT signal transducer and activator of transcription -- SARM selective androgen receptor modulator -- SOD superoxide dismutase -- TNFα tumor necrosis factor -- TWEAK TNFα like weak inducer of apoptosis -- TLR toll-like receptor -- TPA 12-0-tetradecanoylphorbol-13-acetetate -- TGFβ1 transforming growth factor beta 1 -- TSA trichostatin A -- CKD chronic kidney disease -- Activin type II receptor ActRIIB, ActRIIA -- Activin like kinase ALK4, ALK5 -- MuRF1 muscle-specific RING-finger 1; Atrophy -- Cachexia -- Eicosapentaenoic acid -- Resveratrol -- Cox2 inhibitor -- Histone decetylase inhibitor -- Phosphodiesterase inhibitor -- β-Adrenoceptor agonists -- Megestrol acetate -- Anti-cytokines; EPA (PubChem CID: 446284) -- β-Hydroxy-β-methylbutyrate (PubChem CID: 69362) -- Cis-resveratrol (PubChem CID: 1548910) -- Trans-resveratrol (PubChem CID: 445154) -- Ghrelin (PubChem CID: 44576256) -- Celecoxib (PubChem CID: 2662) -- Meloxicam (PubChem CID: 54677470) -- Trichostatin A (PubChem CID: 444732) -- Torbafylline (PubChem CID: 65888) -- Pentoxifylline (PubChem CID: 4740) -- Formoterol (PubChem CID: 3410) -- Clenbuterol (PubChem CID: 2783) -- Enobosarm (PubChem CID: 11326715) -- Thalidomide (PubChem CID: 5426) -- Megestrol acetate (PubChem CID: 11683); Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2015.05.010
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.