Spatial proteomics reveals heterogeneity in neural markers underpinning high-fat diet-induced myopathy in male mice.

Metabolic dysfunction in skeletal muscle disturbs its contractile response as well as its innervation and vascular networks. The molecular drivers responsible for affecting decline in function remain poorly defined. To provide insight and locate these, we mapped changes in the spatial proteome occurring as a result of impaired metabolic health. We exposed male mice (C57/BL6J) to diet induced obesity to investigate the impairment of muscle metabolic function and myopathy. We conducted digital spatial profiling using the NanoString GeoMx(R) platform on recovered skeletal muscle (tibialis anterior) comparing it to standard fed controls. Digital spatial profiling revealed areas with shifts in the contractile protein desmin and CD31 expression, a marker of tissue stress and cellular maladaptation. We find increased expression of proinflammatory markers were identified in areas of elevated Desmin in obese samples compared to controls. Our data suggest a dietary-driven relationship between the spatial abundance of the sarcomere protein desmin and the influx of neural and inflammatory mediators to muscle. This supports the concept of pro-inflammatory events underpinning the muscle metabolic dysfunction associated with chronic non-communicative diseases such as type 2 diabetes, metabolic syndrome, and chronic obstructive pulmonary disorder.