Pathophysiological Mechanisms Explaining the Association Between Low Skeletal Muscle Mass and Cognitive Function
The Journals of Gerontology Series A, vol. 77, pp. 1959–1968
Abstract
Low skeletal muscle mass is associated with cognitive impairment and dementia in older adults. This review describes the possible underlying pathophysiological mechanisms: systemic inflammation, insulin metabolism, protein metabolism, and mitochondrial function. We hypothesize that the central tenet in this pathophysiology is the dysfunctional myokine secretion consequent to minimal physical activity. Myokines, such as fibronectin type III domain containing 5/irisin and cathepsin B, are released by physically active muscle and cross the blood-brain barrier. These myokines upregulate local neurotrophin expression such as brain-derived neurotrophic factor (BDNF) in the brain microenvironment. BDNF exerts anti-inflammatory effects that may be responsible for neuroprotection. Altered myokine secretion due to physical inactivity exacerbates inflammation and impairs muscle glucose metabolism, potentially affecting the transport of insulin across the blood-brain barrier. Our working model also suggests other underlying mechanisms. A negative systemic protein balance, commonly observed in older adults, contributes to low skeletal muscle mass and may also reflect deficient protein metabolism in brain tissues. As a result of age-related loss in skeletal muscle mass, decrease in the abundance of mitochondria and detriments in their function lead to a decrease in tissue oxidative capacity. Dysfunctional mitochondria in skeletal muscle and brain result in the excessive production of reactive oxygen species, which drives tissue oxidative stress and further perpetuates the dysfunction in mitochondria. Both oxidative stress and accumulation of mitochondrial DNA mutations due to aging drive cellular senescence. A targeted approach in the pathophysiology of low muscle mass and cognition could be to restore myokine balance by physical activity.
Authors 6
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Amsterdam Public Health · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Outpatient Clinics, Amsterdam Public Health Research Institute, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
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National University of Singapore · National University Health System
Affiliation as printed
Centre for Healthy Longevity, @AgeSingapore, National University Health System , Singapore , Singapore
Healthy Longevity Translational Research Program and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore , Singapore
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Affiliation as printed
Department of Internal Medicine, Alrijne Hospital , Leiderdorp , The Netherlands
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The Royal Melbourne Hospital · The University of Melbourne · Amsterdam Movement Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Movement Sciences, Ageing and Vitality , Amsterdam , The Netherlands
Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne , Parkville, Victoria , Australia
Rehabilitation Medicine, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
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Amsterdam Movement Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Movement Sciences, Ageing and Vitality , Amsterdam , The Netherlands
Rehabilitation Medicine, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam , The Netherlands
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Andrea Britta Maier corresponding
The Royal Melbourne Hospital · The University of Melbourne · National University of Singapore · National University Health System · Amsterdam Movement Sciences · Vrije Universiteit Amsterdam
Affiliation as printed
Centre for Healthy Longevity, @AgeSingapore, National University Health System , Singapore , Singapore
Department of Human Movement Sciences, @AgeAmsterdam, Faculty of Behavioral and Movement Sciences, VU University Amsterdam, Amsterdam Movement Sciences , Amsterdam , The Netherlands
Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne , Parkville, Victoria , Australia
Healthy Longevity Translational Research Program and Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore , Singapore
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