The function of previously unappreciated exerkines secreted by muscle in regulation of neurodegenerative diseases

Abstract

The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of patients, concurrently exerting a considerable strain on both the economy and the social healthcare infrastructure. Exercise has demonstrated its potential as both an effective preventive intervention and a rehabilitation approach among the emerging therapeutics targeting NDs. As the largest secretory organ, skeletal muscle possesses the capacity to secrete myokines, and these myokines can partially improve the prognosis of NDs by mediating the muscle-brain axis. Besides the well-studied exerkines, which are secreted by skeletal muscle during exercise that pivotally exert their beneficial function, the physiological function of novel exerkines, e.g., apelin, kynurenic acid (KYNA), and lactate have been underappreciated previously. Herein, this review discusses the roles of these novel exerkines and their mechanisms in regulating the progression and improvement of NDs, especially the significance of their functions in improving NDs' prognoses through exercise. Furthermore, several myokines with potential implications in ameliorating ND progression are proposed as the future direction for investigation. Elucidation of the function of exerkines secreted by skeletal muscle in the regulation of NDs advances the understanding of its pathogenesis and facilitates the development of therapeutics that intervene in these processes to cure NDs.

Keywords: KYNA; apelin; exercise; lactate; myokine; neurodegenerative disease.

FIGURE 1

Exercise improves the prognoses of patients with NDs through multiple mechanisms. As aging progresses, there is a conspicuous escalation in the susceptibility to NDs. Physical exercise enhances synaptic plasticity, neurogenesis, epigenetic modifications, and central cerebral blood flow, and mitigates neurodegenerative risk factors linked to age-related glial cell activation, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction via modulation of both classical and neglected myokines. BDNF, brain-derived neurotrophic factor; IGF-1, insulin-like growth factor-1; CTSB, cathepsin B; FNDC5, fibronectin type III domain-containing protein 5; IL-6, interleukin 6.

FIGURE 2

Relationship between exerkines and myokines. Exerkines are factors that are induced by exercise in various organs. Myokines are factors secreted by muscles and not necessarily induced by exercise. As depicted in the figure, a noticeable overlap exists between exerkines and myokines. The overlapping segment represents factors induced in muscles as a result of exercise, which may serve as the molecular foundation for elucidating the health-promoting effects of physical activity.

FIGURE 3

Literature screening process. The first step is to search all the brain and exercise-related muscle factors involved in the review published over the past 5 years and exclude the well-studied factors such as BDNF. The second step is to search the factors and keywords such as ND, exercise, and muscle, and find evidence of muscle secretion into the blood. Three factors with genetic evidence and several factors with partial evidence were identified.

FIGURE 4

Possible pathways for exercise to improve brain health through Apelin. Apelin released in response to exercise binds the G protein-coupled receptor APJ, improving ND pathology through multiple pathways. BBB, blood-brain barrier.

FIGURE 5

The dual role of lactate in central and peripheral functions. Lactate produced by skeletal muscle enters the periphery through MCTs to provide energy, resist lipolysis, promote osteoblast differentiation, and promote muscle hypertrophy. Upon entering the central region, lactate undergoes enzymatic conversion to pyruvate by lactate dehydrogenase, serving as a vital energy source within the tricarboxylic acid cycle (TCA). Concurrently, lactate activates the AMPK/SIRT1/PGC-1α pathways, leading to the mitigation of oxidative stress, inflammation, and apoptosis. In a distinct role, lactate functions as a signaling molecule. A portion of it engages with the lactate receptor GPR81, modulating ERK1/2 signaling, while another portion influences the glutamate receptor NMDAR via intracellular signaling. These integrated actions collectively foster neurogenesis, angiogenesis, and synaptic plasticity, ultimately enhancing the prognosis for patients afflicted by NDs.

FIGURE 6

The improved prognosis of ND patients may be related to the reduction of central toxicity of KP by exercise. Exercise promotes the expression of KATs in skeletal muscle and converts peripheral KYN to KYNA. While peripherally generated KYNA may not exert positive effects by crossing the blood-brain barrier, the reduction of KYN/Trp indirectly lowers central KYN intake, thereby mitigating the central toxicity of the KP metabolites. Additionally, KATs within astrocytes can promote KYNA production, contributing to a range of neuroprotective effects.