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4-PBA prevents diabetic muscle atrophy in rats by modulating ER stress response and ubiquitin-proteasome system

S Sreenivasa Reddy1, Karnam Shruthi1, Dorit Joy1

  • 1Biochemistry Division, National Institute of Nutrition, Hyderabad, India.

Chemico-Biological Interactions
|April 14, 2019
PubMed
Abstract

Insights

4-phenylbutyric acid (PBA) treatment reduced endoplasmic reticulum (ER) stress, the ubiquitin-proteasome system (UPS), and apoptosis in diabetic rats. PBA administration improved muscle atrophy, indicating its therapeutic potential for diabetes-related muscle wasting.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Endocrinology

Background:

  • Diabetes mellitus significantly impacts skeletal muscle, leading to muscle atrophy.
  • Endoplasmic reticulum (ER) stress has been identified as a key contributor to diabetes-induced muscle atrophy.
  • Hyperglycemia in diabetes exacerbates ER stress, further promoting muscle wasting.

Purpose of the Study:

  • To investigate the therapeutic effect of 4-phenylbutyric acid (PBA), a classical ER stress inhibitor, on muscle atrophy in a rat model of diabetes.
  • To determine if PBA can ameliorate ER stress, ubiquitin-proteasome system (UPS) activation, and apoptosis in the skeletal muscle of diabetic rats.

Main Methods:

  • Diabetes was induced in male rats using streptozotocin.
  • 4-phenylbutyric acid (PBA) was administered intraperitoneally to diabetic rats for two months.
  • Gastrocnemius muscle was analyzed for myocyte cross-sectional area, ER stress markers, UPS components, and apoptosis.
  • Proteasomal activity and the number of apoptotic cells were quantified.

Main Results:

  • PBA treatment significantly reduced elevated ER stress markers (GRP78, ATF6, ATF4, CHOP) in diabetic rat muscle.
  • PBA administration attenuated diabetes-induced alterations in the ubiquitin-proteasome system (UPS), including levels of E1, atrogin-1, UCHL1, UCHL5, ubiquitinated proteins, and proteasomal activity.
  • PBA decreased the expression of apoptosis mediators (p53, BAX, cleaved caspase-3) and the number of TUNEL-positive cells in diabetic muscle.
  • Notably, PBA treatment improved the muscle cross-sectional area in diabetic rats.

Conclusions:

  • 4-phenylbutyric acid (PBA) effectively mitigates ER stress, UPS activation, and apoptosis in skeletal muscle of diabetic rats.
  • PBA demonstrates significant therapeutic potential in combating diabetes-induced muscle atrophy.
  • Targeting ER stress with PBA offers a promising strategy for managing muscle wasting in diabetes.
Keywords:
ApoptosisDiabetesER stressMyopathySkeletal muscleUbiquitin-proteasome system

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