Mechanisms of Neuroprotection Arising from Exercise
Muscle tissue is metabolically active. In response to use during physical activity, muscle cells secrete a range of signals, as a class now called myokines or exerkines. These signals produce overall beneficial effects on cell behavior and tissue function throughout the body. The precise details of this process are still under investigation, and only the major signals are fairly well mapped - a great deal remains to be discovered in terms of exactly how exercise improves function. Here, researchers review what is presently known of this connection between exercise and a slowing of the progression of age-related neurodegeneration. The research community is quite interested in producing exercise mimetic therapies of various sorts, and one approach to that goal is the identification of specific signals or responses to those signals that can be manipulated.
Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, driven by dopaminergic loss and α-synuclein accumulation. Beyond neurodegeneration, growing evidence highlights skeletal muscle health as a key determinant of prognosis, with sarcopenia and frailty contributing to greater disability, fall risk, and reduced quality of life. This narrative review synthesizes current evidence on the interplay among exercise, muscle status, and exerkine signaling in PD, emphasizing their potential roles in neuroprotection and functional outcomes.
Sarcopenia and reduced muscle strength are highly prevalent in PD and independently associated with disease severity, frailty, and falls, while grip strength has emerged as a simple biomarker of progression. Clinical trials consistently show that aerobic, resistance, and multimodal exercise programs improve gait, balance, mood, cognition, and quality of life, with progressive resistance and balance training yielding the greatest motor benefits.
At a mechanistic level, skeletal muscle functions as an active endocrine organ, releasing a variety of exercise-induced signaling molecules known as exerkines. These include brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), irisin, cathepsin B, myostatin, and growth/differentiation factor 15 (GDF15). Together, these exerkines facilitate muscle-brain crosstalk and are thought to contribute to the neuroprotective effects of exercise in PD. Through anti-inflammatory, antioxidant, and mitochondrial regulatory pathways, they support dopaminergic neuron survival and promote synaptic plasticity and neuronal resilience.