Fractalkine is a key player in skeletal muscle metabolism and pathophysiology.

Fractalkine (CX3CL1) is increasingly recognised for its role in regulating the metabolism of various tissues, including skeletal muscle. The circulating level of CX3CL1 is influenced by multiple organs including the brain, adipose tissue and immune cells, with skeletal muscles emerging as a significant source. Growing evidence shows that CX3CL1 modulates muscle metabolism through autocrine and paracrine mechanisms as well as influencing properties (i.e. migration, secretion, cellular communication) of local immune cells. Within skeletal muscle, CX3CL1-signaling is involved in the regulation of fibre-type composition, mitochondrial remodeling, local inflammation, and regenerative capacity. These actions affect muscle plasticity and adaptability in both resting and active states. CX3CL1 also facilitates substrate uptake, particularly glucose and lipids, by interacting synergistically with insulin-signaling pathways, especially during metabolic stress or exercise. Furthermore, CX3CL1 contributes to the coordination of skeletal muscle function with other key metabolic organs such as adipose tissue, liver and brain. Notably, CX3CL1 appears to play a role in the pathogenesis of several chronic diseases, including type 2 diabetes (T2D), obesity, cardiovascular disease (CVD), insulin resistance (IR) and arthritis. These findings underscore the relevance of CX3CL1 in both health and disease. Here, we critically assess recent advances in CX3CL1 research, including its mechanism of action, and explore its potential implications in physiological and pathological scenarios.