Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls

Abstract

Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping. In contrast, dietary supplements with a higher safety margin exert milder outcomes. In recent years, the design of pharmacological agents that activate the training program, so-called "exercise mimetics", has been proposed, although the feasibility of such an approach is highly debated. In this review, the most recent insights into key regulatory factors and therapeutic approaches aimed at leveraging exercise adaptations are discussed.

Keywords: AICAR (PubChem CID 266934); AMPK; Citrulline malate (PubChem CID 162762); Cpd14 (PubChem CID not available); Creatine (PubChem CID 586); Dietary supplements; Exercise; Exercise mimetics; GW501516 (PubChem CID 9803963); L-citrulline (PubChem CID 9750); MK-8722 (PubChem CID not available); Metformin (PubChem CID 4091); PF-739 (PubChem CID not available); PGC-1α; PPARβ/δ; R419 (PubChem CID not available); Rapamycin (PubChem CID 5284616); SR-18292 (PubChem CID not available); Scriptaid (PubChem CID 5186); Skeletal muscle; mTOR; β-Hydroxy β-methylbutyric acid (HMB) (PubChem CID 69362).

Fig. 1. Different exercise modalities and pharmaceutical compounds modulate mitochondrial function.

Endurance exercise leads to the activation of AMPK and consequently to increased coactivation of PPARβ/δ by PGC-1α, resulting in improved mitochondrial oxidative function. Different pharmacological compounds may activate this pathway even in absence of endurance exercise and at least partially confer endurance performance benefits. Resistance exercise activates mTORC1 and increases coactivation of YY1 by PGC-1α, presumably via phosphorylation of S6K (ribosomal protein S6 kinase). This also affects mitochondrial function. Rapamycin and other pharmacologic inhibitors of mTORC1, but also exercise interference can blunt this response. Exercise interference is a controversially discussed mechanism by which concurrent endurance exercise may negatively impact adaptations to resistance exercise by decreasing mTORC1 activity. AICAR, R419, Cpd14, Mk-8722, and Metformin are (potential) pharmacologic AMPK activators. GW501516 is a known pharmacologic PPARβ/δ activator. Arrows indicate activation, dashed lines indicate inhibition.

Fig. 2. Pharmacological modulation of PGC-1α acetylation affects the interaction with transcription factor bindings partners.

PGC-1α expression is increased in the diabetic liver, where it interacts with and coactivates HNF-4α to boost expression levels of the gluconeogenic genes PCK1 and G6PC. The result is increased hepatic glucose production that negatively effects the diabetic phenotype. The compound SR-18292 reduces the interaction between PGC-1α and HNF-4α by increasing PGC-1α acetylation, resulting in lower PCK1 and G6PC levels, reduced hepatic glucose production, and thus amelioration of the diabetic phenotype. SR-18292, as well as similar compounds modifying hepatic PGC-1α-HNF-4α interactions, could therefore prove to be effective treatment options in T2DM.