Muscle injury and impaired function, and insulin resistance in Chromogranin A knockout mice

32 33 Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central 34 nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and 35 found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation 36 with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal 37 muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and 38 phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), 39 (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines 40 Tnfα, Il6 and Ifnɣ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in 41 Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and 42 decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated 43 with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. Since CgA 44 sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of 45 membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular 46 aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy 47 deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue 48 damage. 49 50 Page 2 of 43