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Melatonin treatment combined with treadmill exercise accelerates muscular adaptation through early inhibition of CHOP ‐mediated autophagy in the gastrocnemius of rats with intra‐articular collagenase‐induced knee laxity
Author(s) -
Hong Yunkyung,
Kim JooHeon,
Jin Yunho,
Lee Seunghoon,
Park Kanghui,
Lee Youngjeon,
Chang KyuTae,
Hong Yonggeun
Publication year - 2014
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12110
Subject(s) - endocrinology , melatonin , medicine , collagenase , gastrocnemius muscle , chop , chemistry , skeletal muscle , enzyme , biochemistry , lymphoma
The purpose of this study was to determine the effects of melatonin intervention on gastrocnemius remodeling in rats with collagenase‐induced knee instability. Type VII collagenase was injected into the right knee to induce joint laxity with cartilage destruction. Melatonin ( MT ; 10 mg/kg) injection was performed twice daily subcutaneously, and treadmill exercise (Ex; 11 m/min) was conducted for 1 hr/day at a frequency of 5 days/wk for 4 wks. The gastrocnemius mass, which was reduced with collagenase injection only ( V eh), was increased with collagenase injection with melatonin treatment with and without exercise in the early phase, and the mass in both limbs was significantly different in the V eh compared with the MT group. However, there was an increase in the relative muscle weight to body weight ratio in the V eh group at the advanced stage. Insulin‐like growth factor receptor ( IGF ‐ IR ) was downregulated in the V eh group, whereas IGF ‐ IR was upregulated in the MT and MT + Ex groups. Joint laxity induced enhancement of autophagic proteolysis ( LC 3 II ) in the muscle, which was recovered to values similar to those in the normal control group ( C on) compared with those in the MT and MT + Ex groups. Although intra‐articular collagenase increased the total C / EBP homology protein ( CHOP ) levels at 1 wk and decreased them at 4 wks in the V eh group, CHOP in the nucleus was upregulated continuously. Prolonged melatonin treatment with and without exercise intervention suppressed nuclear localization of ATF 4 and CHOP with less activation of caspase‐3, at the advanced phase. Moreover, the interventions promoted the expression of myosin heavy chain ( MHC ) isoforms under the control of myogenin. Concomitant with a beneficial effect of melatonin with and without exercise, step length of the saline‐injected limb and the collagenase‐injected supporting side was maintained at values similar to those in control rats. Taken together, the findings demonstrate that melatonin with and without exercise accelerate remodeling of the gastrocnemius through inhibition of nuclear CHOP in rats with collagenase‐induced knee instability.