Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis - Potential implications for sports drug testing programs.

Abstract

A plethora of compounds potentially leading to drug candidates that affect skeletal muscle function and, more specifically, mitochondrial biogenesis, has been under (pre)clinical investigation for rare as well as more common diseases. Some of these compounds could be the object of misuse by athletes aiming at artificial and/or illicit and drug-facilitated performance enhancement, necessitating preventive and proactive anti-doping measures. Early warnings and the continuous retrieval and dissemination of information are crucial for sports drug testing laboratories as well as anti-doping authorities, as they assist in preparation of efficient doping control analytical strategies for potential future threats arising from new therapeutic developments. Scientific literature represents the main source of information, which yielded the herein discussed substances and therapeutic targets, which might become relevant for doping controls in the future. Where available, mass spectrometric data are presented, supporting the development of analytical strategies and characterization of compounds possibly identified in human sports drug testing samples. Focusing on skeletal muscle and mitochondrial biogenesis, numerous substances exhibiting agonistic or antagonistic actions on different cellular 'control centers' resulting in increased skeletal muscle mass, enhanced performance (as determined with laboratory animal models), and/or elevated amounts of mitochondria have been described. Substances of interest include agonists for REV-ERBα (e.g. SR9009, SR9011, SR10067, GSK4112), sirtuin 1 (e.g. SRT1720, SRT2104), adenosine monophosphate-activated protein kinase (AMPK, e.g. AICAR), peroxisome proliferator-activated receptor (PPAR)δ (e.g. GW1516, GW0742, L165041), and inhibitory/antagonistic agents targeting the methionine-folate cycle (MOTS-c), the general control non-derepressible 5 (GCN5) acetyl transferase (e.g. CPTH2, MB-3), myostatin (e.g. MYO-029), the myostatin receptor (bimagrumab), and myostatin receptor ligands (e.g. sotatercept, ACE-031). In addition, potentially relevant drug targets were identified, e.g. with the sarcoplasmic transmembrane peptide myoregulin and the nuclear receptor corepressor 1 (NCOR-1). The antagonism of these has shown to result in substantially enhanced physical performance in animals, necessitating the monitoring of strategies such as RNA interference regarding these substances. Most drug candidates are of lower molecular mass and comprise non-natural compositions, facts which suggest approaches for their qualitative identification in doping control samples by mass spectrometry. Electrospray ionization/collision-induced dissociation mass spectra of representatives of the aforementioned substances and selected in vitro derived phase-I metabolites support this assumption, and test methods for a subset of these have been recently established. Expanding the knowledge on analytical data will further facilitate the identification of such analytes and related compounds in confiscated material as well as sports drug testing specimens.