Invited reviewHow does the skeletal muscle communicate with the brain in health and disease?
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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2023, Neuroscience and Biobehavioral ReviewsDoes the regulation of skeletal muscle influence cognitive function? A scoping review of pre-clinical evidence
2023, Journal of Orthopaedic TranslationCitation Excerpt :Diverse whole-body treatments have been raised to promote both muscle and brain functions, and exercise is one of the hotspots [21,50]. As muscle is an endocrine organ, the key points in observing the role of muscle in these kinds of treatments is to discover the muscle-derived molecules, which can be assisted by modern sequencing analysis [28]. In addition to muscle, exercise can also benefit other organs, such as liver and adipose tissue [50].
Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process
2022, Ageing Research ReviewsCitation Excerpt :Exercise is gradually accepted and confirmed as an important intervention to prevent and control nervous system diseases, and its important mechanisms may involve exercise-induced metabolic and physiological changes, and the release of myokines such as FNDC5/irisin and IL-6. These factors may participate in the production, development, and repair of damaged neurons (de Freitas et al., 2020; Isaac et al., 2021; Chow et al., 2022). Therefore, focusing on these factors that have functional activity on the nervous system may become an important evaluation index for the health of the nervous system.