In the clinical setting, anabolic agents serve to ameliorate muscle- and bone-wasting diseases. However, many of these anabolic agents are also used by bodybuilders to surpass natural limits of body composition as performanceenhancing drugs (PEDs). The first generation of PEDs comprises testosterone-derived anabolic-androgenic steroids (AAS) which have demonstrated significant myotropic effects. However, AAS lack optimal tissue-selectively and thus, are prone to numerous adverse health consequences. Hence, a newer generation of PEDs, selective androgen receptor modulators (SARMs), was developed with the goal of achieving superior tissue-selectivity (i.e., exerting anabolic effects only in muscle and bone tissue, while minimally affecting other body systems). In general, AAS and SARMs enhance muscle growth primarily through androgen receptor (AR) agonism in target tissues. Despite multiple attempts, no single AAS nor SARM to date is completely risk free. As such, a significant portion of research efforts has been dedicated to manipulating anabolic pathways beyond the AR. Another class of PEDs, myostatin inhibitors, have shown to cause drastic muscle anabolism across multiple species by inhibiting myostatin, the primary deterrent to continuous muscle growth. The myostatin inhibitor, YK-11, blocks myostatin by upregulating its antagonist, follistatin. This effect appears to be mediated through the AR, suggesting a novel and promising gene-selective approach to engineering AR ligands that isolate benefits from risks. At any rate, the exact mechanisms by which these PEDs function is not well understood. Further pioneering regarding these topics is encouraged as it appears that the innovation of a truly tissue-selective anabolic agent is within reach.

A complex network of biochemical pathways carries out the process of muscle regeneration/growth following resistance exercise. The initial inflammatory response following muscle damage is primarily mediated by the nuclear factor κ -light-chain-enhancer of activated B cells (NF-κ B), cyclooxygenase enzymes, and prostaglandins. Muscle damage also stimulates the activation, proliferation, differentiation, migration, and fusion of satellite cells onto damaged myofibers, resulting in myofibrillar hypertrophy. The progression of the myogenic lineage is predominantly coordinated by the wingless/integrated family of glycoproteins which engages in crosstalk with NF-κ B and the mitogen-activated protein kinase (MAPK)/extracellular signaling-regulated kinase network. The MAPK cascade is essential for mechanotransduction, the process of converting mechanical stimuli into biochemical responses such as accelerated protein synthesis and satellite cell activation. Muscle protein synthesis is primarily governed by the insulin-like growth factor 1/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Several calcium-dependent pathways are also integrated into the process of myogenesis and influence skeletal muscle plasticity. These dynamic interactions are part of the anabolic priming by resistance exercise effect, which defines resistance exercise as an acute catabolic event that potentiates multiple downstream anabolic pathways.Plateaus in muscle growth are attributed to deteriorating inflammatory signaling with repeated bouts of muscle damage as well as increasing thresholds for continuous adaptations, which ultimately become unreachable beyond a certain point. The physiological ceiling of skeletal muscle mass is also credited to myostatin. However, recent discoveries suggest the role of myostatin is not limited to preventing excessive skeletal muscle hypertrophy.