1. Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice
- Author
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Angelo Corti, Sushil K. Mahata, Jennifer Tang, Sumana Mahata, Nai-Wen Chi, Kechun Tang, Angshuman Biswas, Amiya P. Sinha-Hikim, Teresa Pasqua, Alisa Tang, Nicholas J. G. Webster, Gautam Bandyopadhyay, Tang, Kechun, Pasqua, Teresa, Biswas, Angshuman, Mahata, Sumana, Tang, Jennifer, Tang, Alisa, Bandyopadhyay, Gautam K., Sinha Hikim, Amiya P., Chil, Nai Wen, Webster, Nicholas J. G., Corti, Angelo, and Mahata, Sushil K.
- Subjects
0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Stimulation ,Mitochondrion ,p38 Mitogen-Activated Protein Kinases ,Mice ,0302 clinical medicine ,Endocrinology ,Fibrosis ,2.1 Biological and endogenous factors ,Glycolysis ,Phosphorylation ,Aetiology ,Tubular aggregate ,Mice, Knockout ,biology ,Chromogranin A ,Skeletal ,Physical Conditioning ,Mitochondria ,medicine.anatomical_structure ,Muscle ,Signal Transduction ,endocrine system ,medicine.medical_specialty ,Knockout ,glucose metabolism ,1.1 Normal biological development and functioning ,Clinical Sciences ,Article ,Electron Transport Complex IV ,Endocrinology & Metabolism ,03 medical and health sciences ,Insulin resistance ,Animal Production ,Underpinning research ,Physical Conditioning, Animal ,Internal medicine ,medicine ,Animals ,Veterinary Sciences ,skeletal muscle ,Muscle, Skeletal ,insulin signaling ,Animal ,Prevention ,Skeletal muscle ,medicine.disease ,Insulin receptor ,Glucose ,030104 developmental biology ,biology.protein ,tubular aggregates ,Insulin Resistance ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficientChga-KO mice in treadmill exercise was impaired. Supplementation with CgA inChga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function.Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokinesTnfα,Il6andIfnγ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise inChga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed inChga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage.
- Published
- 2017