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

Authors

  • Yunkyung Hong,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
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    • These authors contributed equally to this work.
  • Joo-Heon Kim,

    1. Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
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    • These authors contributed equally to this work.
  • Yunho Jin,

    1. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    2. Department of Physical Therapy, Graduate School of Inje University, Gimhae, Korea
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  • Seunghoon Lee,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
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  • Kanghui Park,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Division of Rehabilitation Medicine, Dongwei Medical Center, Busan, Korea
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  • Youngjeon Lee,

    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
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  • Kyu-Tae Chang,

    Corresponding author
    1. National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
    • Address reprint request to Yonggeun Hong, Department of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeong-nam 621-749, Korea.

      E-mail: yonghong@inje.ac.kr

      Kyu-Tae Chang, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro 30, Ochang, Chung-buk 363-883, Korea.

      E-mail: changkt@kribb.re.kr

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  • Yonggeun Hong

    Corresponding author
    1. Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea
    2. Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea
    3. Department of Physical Therapy, Graduate School of Inje University, Gimhae, Korea
    4. Ubiquitous Healthcare Research Center (UHRC), Inje University, Gimhae, Korea
    • Address reprint request to Yonggeun Hong, Department of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeong-nam 621-749, Korea.

      E-mail: yonghong@inje.ac.kr

      Kyu-Tae Chang, National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro 30, Ochang, Chung-buk 363-883, Korea.

      E-mail: changkt@kribb.re.kr

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Abstract

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 (Veh), 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 Veh compared with the MT group. However, there was an increase in the relative muscle weight to body weight ratio in the Veh group at the advanced stage. Insulin-like growth factor receptor (IGF-IR) was downregulated in the Veh group, whereas IGF-IR was upregulated in the MT and MT + Ex groups. Joint laxity induced enhancement of autophagic proteolysis (LC3 II) in the muscle, which was recovered to values similar to those in the normal control group (Con) 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 Veh group, CHOP in the nucleus was upregulated continuously. Prolonged melatonin treatment with and without exercise intervention suppressed nuclear localization of ATF4 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.

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