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Defective autophagy causes a maladaptive cardiac phenotype to exercise that leads to premature death and FGF21‐mediated protection against obesity and insulin resistance
Author(s) -
Lira Vitor A.,
Kronemberger Ana,
Call Jarrod A.,
Caster Hannah M,
Pereira Renata O.,
Laker Rhianna C.,
Zhang Mei,
Yan Zhen
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1014.4
Subject(s) - autophagy , insulin resistance , endocrinology , medicine , skeletal muscle , muscle hypertrophy , cardiac fibrosis , cardiac muscle , insulin , fibrosis , biology , biochemistry , apoptosis
Autophagy is induced by exercise in skeletal and cardiac muscle. Skeletal muscle autophagy is required for exercise‐induced metabolic adaptations; yet, impaired skeletal muscle autophagy may cause a compensatory ER stress response that protects against diet‐induced obesity and insulin resistance. The functional importance of cardiac autophagy to the benefits of exercise is uncertain. Here, we generated heart & muscle‐specific Atg7 knockout (Atg7 h&mKO ) mice to gain further insight into this apparent paradox related to skeletal muscle autophagy and to define the role of cardiac autophagy in exercise‐induced protection against obesity and insulin resistance. Despite exhibiting minimal autophagy in skeletal muscle and heart, Atg7 h&mKO mice presented normal exercise capacity and glucose tolerance with a slight reduction in body weight (~5%) at 12–14 weeks of age. After 12 weeks on high‐fat diet (60% calories from fat) sedentary Atg7 h&mKO mice gained weight and developed insulin resistance like control littermates (Atg7 fl/fl ). Exercise (voluntary wheel running) reduced the degree of diet‐induced obesity and glucose intolerance in Atg7 h&mKO mice more efficiently; but surprisingly led to premature death of ~40% of these animals. This reduced survival was likely caused by a maladaptive cardiac phenotype as exercise induced physiological cardiac hypertrophy and prevented diet‐induced fibrosis in the hearts of Atg7 fl/fl , whereas it exacerbated fibrosis and caused pathological hypertrophy in the hearts of Atg7 h&mKO . Interestingly, this maladaptive cardiac phenotype to exercise was accompanied by improved skeletal muscle insulin sensitivity, increased Glut4 mRNA in adipose tissues, and elevated Pgc‐1a and Ucp1 mRNA in brown adipose tissue of Atg7 h&mKO suggesting a potential cross‐talk between the heart and peripheral tissues. Analysis of serum indicated a robust increase in circulating FGF21 levels in Atg7 h&mKO that exercised, which were accompanied by marked upregulation of Fgf21 mRNA expression exclusively in the heart. Examination of β‐Klotho mRNA, a co‐receptor required for FGF21 signaling, revealed a ~2‐fold upregulation exclusively in white and brown adipose tissues. Our results indicate that autophagy plays a critical role in exercise‐induced protection against cardiac dysfunction in obesity and diabetes. Impaired cardiac autophagy causes a maladaptive phenotype to exercise that leads to premature death, but also potentiates the peripheral metabolic benefits of exercise, at least in part, via a heart‐adipose tissue signaling axis involving FGF21. Support or Funding Information Obesity Research and Education Initiative (OREI) and the Fraternal Order of Eagles Diabetes Research Center (FOEDRC) at the University of Iowa (V.A.L.) and U.S. National Institutes of Health (NIH) grant AR050429 (Z.Y.)