Sympathetic nervous system-mediated fibro-adipogenic progenitor mobilization drives stroke-related sarcopenia.

Patients who survive stroke usually experience rapid muscle wasting and an increased risk of physical disability. Although multifactorial interactions, including malnutrition, disuse, systemic catabolic imbalance, and neurohormonal dysregulation, are thought to contribute to the progression of stroke-related sarcopenia, the underlying mechanisms of this brain-muscle crosstalk remain elusive. Muscle-resident fibro-adipogenic progenitors (FAPs) are indispensable for maintaining muscle homeostasis and function as initial sensors of external perturbations. In the present study, we report that FAPs rapidly respond to the overactive sympathetic nervous system (SNS) and egress from the muscle niche into circulation during the acute phase of stroke. FAP-specific ablation of adrenoceptor beta 2 (Adrb2) markedly ameliorated stroke-related sarcopenia, highlighting the central role of SNS-mediated FAP loss in its pathogenesis. Mechanistically, increased norepinephrine release initiates FAP mobilization through the activation of pro-migratory signals and the degradation of extracellular matrix components. Using transcriptomic profiling, we further characterized insulin growth factor-1 (IGF-1) as a key anti-atrophic executive factor predominantly derived from FAPs. Collectively, our work demonstrates that the SNS-mediated loss of FAPs and subsequent compromised IGF-1 secretion contribute to sarcopenia in mice following stroke. Targeting this mechanism by early anti-sympathetic treatment with propranolol may effectively restore muscle homeostasis and mass after stroke.