The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection

Abstract

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer’s disease, or the most common neurodegenerative motor disorder, Parkinson’s disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle–brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle–brain axis in neurodegenerative diseases are outlined.

Effect of Exercise on Secondary Sarcopenia: A Comprehensive Literature Review

“…An overview of a study examined the role of mitochondria in the pathways from muscle to the brain induced by exercise. Among these routes are circulating factors, such as myokines, whose release is often influenced by the mitochondria, as well as direct mitochondrial transfer [ 63 ]. The remodeling of neuromuscular junctions (NMJs), as well as age-related neurophysiological changes may also contribute to neuromuscular impairment [ 64 ].…”

β-Aminoisobutyric acid, L-BAIBA, protects PC12 cells from hydrogen peroxide-induced oxidative stress and apoptosis via activation of the AMPK and PI3K/Akt pathway

“…Exercise is known to have beneficial effects on cognitive disease and neurodegenerative disease, such as Alzheimer disease and Parkinson’s disease ( Ahlskog, 2011 , Ellis and Rochester, 2018 , Mattson, 2012 , Valenzuela et al, 2020 ). Various mechanisms of the beneficial effects by exercise in neuronal diseases are considered such as direct exercise effects, indirect exercise effects, improvement of mitochondrial function and release of circulating factors from skeletal muscles ( Burtscher et al, 2021 ).…”

Disentangling Mitochondria in Alzheimer’s Disease

“…Regular endurance exercise improves mitochondrial health, mitochondrial plasticity, and mitochondrial biogenesis and respiration [ 286 , 287 ]. It also enhances antioxidant capacities and the affinity of mitochondria for oxygen, improving healthy aging ([ 288 , 289 , 290 , 291 ] and references therein). Moderate-to-high-intensity exercise reduced neuropsychiatric symptoms in patients with mild AD and preserved cognition in a subgroup of patients exercising with high attendance and intensity [ 292 ].…”

“…Therefore, lifestyle modifications, including diet and exercise, are another avenue being pursued, with similar success as the mitochondria-targeted compounds. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD [ 291 , 348 , 349 , 350 , 351 , 352 , 353 ]. Based on the review of literature presented above, I conclude that a combination of mitochondria-targeted antioxidants with diet and exercise interventions may achieve desirable treatment efficacy and could be the way to proceed in the future.…”