Elsevier

Neuropharmacology

Volume 197, 1 October 2021, 108744
Neuropharmacology

Invited review
How does the skeletal muscle communicate with the brain in health and disease?

https://doi.org/10.1016/j.neuropharm.2021.108744Get rights and content

Highlights

  • Muscle-derived molecules play key roles in cognition and mood.

  • Myokines trigger signaling mechanisms that favor synapse plasticity in the brain.

  • Metabolic disorders and skeletal muscle disease may impair brain function.

  • Physical exercise may boost muscle-brain communication, cognition and mood.

Abstract

Endocrine mechanisms have been largely associated with metabolic control and tissue cross talk in mammals. Classically, myokines comprise a class of signaling proteins released in the bloodstream by the skeletal muscle, which mediate physiological and metabolic responses in several tissues, including the brain. Recent exciting evidence suggests that myokines (e.g. cathepsin B, FNDC5/irisin, interleukin-6) act to control brain functions, including learning, memory, and mood, and may mediate the beneficial actions of physical exercise in the brain. However, the intricate mechanisms connecting peripherally released molecules to brain function are not fully understood. Accumulating findings further indicates that impaired skeletal muscle homeostasis impacts brain metabolism and physiology. Here we review recent findings that suggest that muscle-borne signals are essential for brain physiology and discuss perspectives on how these signals vary in response to exercise or muscle diseases. Understanding the complex interactions between skeletal muscle and brain may result in more effective therapeutic strategies to expand healthspan and to prevent brain disease.

This article is part of the special Issue on ‘Cross Talk between Periphery and the Brain’.

Introduction

Mounting evidence indicates that the skeletal muscle releases a myriad of signaling molecules induced by contraction, cell proliferation/differentiation, and/or local metabolic processes (Pedersen, 2019). Since the identification of interleukin-6 (IL-6) as a cytokine released in the bloodstream in response to muscle contraction (Starkie et al., 2001; Steensberg et al., 2000; Ullum et al., 1994), several muscle-derived molecules with signaling actions have been identified (Febbraio and Pedersen, 2020). Therefore, the skeletal muscle has now been referred to as an endocrine organ.

Classically, myokines are defined as proteins that transmit messages from the skeletal muscle to several tissues, including adipose tissue, liver, pancreas, bone, and brain (Febbraio and Pedersen, 2020). Here, we propose to expand this concept to other types of molecules, including metabolites such as lactate and ketone bodies, as they are key contributors of muscle-to-brain communication. Together, signals mediated by myokines are essential to maintain proper body metabolism and physiology in response to a changing environment that includes variations in nutrient availability and physical demands, among others. While the endocrine mechanisms triggered by the skeletal muscle to communicate with peripheral tissues have been thoroughly studied for decades, only recently muscle signals targeting the brain began to be further investigated.

A large body of evidence supports the notion that physical exercise improves learning, memory and attention (Cotman and Berchtold, 2002), sleep, appetite regulation and mood (Blundell et al., 2015; Crush et al., 2018; Kelley and Kelley, 2017) in healthy subjects, in addition to correcting disease phenotypes and symptoms in a number of neurological disorders (de Freitas et al., 2020; Mattson, 2012; van Praag et al., 2014). Although exercise directly impacts the brain, there is now considerable body of findings supporting that a muscle-brain cross talk mediates the physiological responses and the beneficial effects of exercise. More recently, the term exerkine has been coined to encompass endocrine factors that are stimulated by physical exercise (Safdar and Tarnopolsky, 2017).

Herein we review recently described roles for muscle-derived molecules in memory, cognition, and mood, and discuss the exciting perspective that harnessing the potential of myokines and exerkines may be key to modulate brain function. Understanding the intricate processes mediating muscle-brain crosstalk may result in strategies to expand health span and to ward off brain disease.

Section snippets

The muscle as an endocrine tissue

The skeletal muscle is amongst the largest organs in the human body and represents an essential component of the locomotor system, being responsible for maintaining postural support, promoting force and power during voluntary movements, and for supporting involuntary actions, such as breathing and reflex (Frontera and Ochala, 2014). The first evidence of the muscle as an endocrine tissue came out when it was described that contracting muscles release signaling molecules, such as cytokines and

Roles of muscle-derived signals in cognition and mood

While the functions of myokines in regulating peripheral metabolism and physiology have been considerably appreciated, increasing findings propose that these signaling molecules play key roles in neuronal homeostasis in response to physical exercise. A very recent study using tissue specific metabolic labeling followed by proteomics in Drosophila identified 51 muscle-secreted proteins in the fly head (Droujinine et al., 2020), suggesting that the pool of secreted factors mediating muscle to

Indirect paths from muscle to brain

In complement to muscle-derived molecules that have direct effects in the brain, it is conceivable that muscle-initiated processes trigger indirect consequences to the brain via endocrine and metabolic regulation. Metabolic demands by the skeletal muscle upon exercise promote the liver-mediated synthesis and plasma release of ketone bodies, mainly acetoacetate and D-β-hydroxybutyrate (DBHB). DBHB, for instance, crosses the BBB and accumulates in the hippocampus to stimulate histone acetylation

Muscle-brain axis in energy metabolism

Various signals work collectively to regulate eating behavior and nutrient sensing in mammals (Smeets et al., 2012). In the brain, the hypothalamus is one of the most important centers linked to energy metabolism, notably working as a glucose and hormone sensor (Fioramonti et al., 2017). Systemic glucose levels are detected by specialized neurons that trigger signals locally and to the periphery to maintain homeostasis (Fioramonti et al., 2017; Li et al., 2020; Zhou et al., 2018).

In addition to

Does skeletal muscle disease impact the brain?

The key endocrine roles of the skeletal muscle pose the question of whether diseases that distress the muscle could trigger deleterious impacts on brain function. Clinical evidence indicates that humans affected by sarcopenia, a condition of muscle atrophy, present neuroanatomical abnormalities consistent with neurodegeneration (Kwak et al., 2019) and are at increased odds of developing cognitive impairment than matched controls (Chang et al., 2016; Peng et al., 2020). This is consistent with

Tuning muscle-brain cross talk through physical exercise

The molecular scenario of muscle to brain communication raises the prospect that harnessing muscle physiology through exercise might comprise an effective approach to promote brain health. Evidence from randomized trials suggests that it improves memory, processing speed and executive function, notably in children and elderly (Chang et al., 2012; Erickson et al., 2019), and prevent cognitive decline (Beckett et al., 2015; Brasure et al., 2018; Sofi et al., 2011).

A single bout of exercise was

Conclusions

In summary, several candidate molecules have now been proposed to mediate muscle-brain communication (Fig. 1), thereby representing powerful alternatives for the prevention or treatment of neurological disorders. Most of these candidates have emerged from studies investigating the endocrine mechanisms of physical exercise. Nonetheless, it is conceivable that proper muscle-to-brain signaling is an essential physiological mechanism that, once disrupted, may contribute to defective endocrine

Acknowledgements

Work in our laboratory has been supported by grants from the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (434093/2018-1 and 311487/2019-0 to MVL), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (202.744/2019 and 010.002421/2019 to MVL), and by Alzheimer's Association (AARG-D-615741 to MVL), the International Society for Neurochemistry (ISN) (CAEN 1B to MVL), and the International Brain Research

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