Exercise, exerkines, and muscle–brain crosstalk in Parkinson's disease

Abstract 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. A comprehensive literature search in PubMed and SciELO up to October 2025 identified 129 relevant studies, including experimental, observational, and interventional data. 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. Current international guidelines recommend individualized, multimodal programs integrating aerobic, resistance, and balance training, initiated early and maintained long‐term. Exercise represents a promising, nonpharmacological intervention to mitigate neurodegeneration, sarcopenia, and functional decline in PD, although further high‐quality studies are needed.