Abstract

Over the previous decade, there has been growing and fervent interest in scientific and commercial circles regarding the potential of bioactive compounds that mimic, or augment, the effects of exercise. These developments have given rise to the moniker ‘exercise pills’ or ‘exercise mimetics’. The emergence of such orally-delivered bioactive compounds could hold substantial therapeutic value for combating metabolic disease. Such treatments might also present therapeutic value for morbidly obese individuals or those recovering from severe injury. This topic is not without controversy, however, as the search for a ‘one size fits all’ solution is not likely to bear fruit, given the complexity of the molecular and physiological mechanisms involved. The primary goal of this chapter is to explore the challenges of designing a pill that might reliably deliver the myriad and complex adaptations afforded by exercise training, with a focus on skeletal muscle. Furthermore, it will consider the issues, rationale, and practicality of implementing such therapeutics as a credible substitute to engaging in regular exercise training.

Highlights

  • Physical exercise is recognized as a highly effective non-pharmaceutical intervention for a range of health conditions in humans

  • ERRγ is a prominent target for exercise mimetics because of its direct regulation of genes associated with mitochondrial oxidation, there is a paucity of research on the topic [12]

  • Exercise mimetics remains an area of considerable effort and inquiry but is not without its challenges and controversies

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Summary

Introduction

Physical exercise is recognized as a highly effective non-pharmaceutical intervention for a range of health conditions in humans. Systematic review evidence (comprising millions of participants) has indicated that engagement in regular physical exercise is associated with a reduced risk for all-cause mortality, and in a dose-response manner [1] It has important benefits in the prevention and treatment of a range of chronic metabolic conditions [1], such as cardiovascular disease [2], diabetes [3], and cancer [4]. This work has led to the emergence of chemical interventions that can induce the beneficial aspects of exercise, without necessitating actual skeletal muscle activity [15] Such pharmacologic interventions may represent a viable strategy for addressing metabolic diseases associated with physical inactivity [16] or serve as an intermediary treatment for the morbidly obese or people recovering from serious injury [17]. The mechanistic basis for this supposition, and the opportunities and difficulties associated with such a strategy are the focal considerations of this chapter

The identification of cellular and molecular targets in skeletal muscle
The AMPK-SIRT1-PGC1α pathway
PGC1-α
ERRα/γ
REV-ERBα
AMPK activators
Resveratrol
GW501516
GSK4716
SR9009
The challenges and controversies of developing an ‘exercise pill’
Can physical exercise be realistically replaced?
Doping implications for elite athletes
Side effects of human metabolic modulators
Non-pharmacological ‘exercise mimetic’ alternatives
Findings
Conclusions
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