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Impaired Mitochondrial Clearance Contributes to Heat Stress‐mediated Muscle Dysfunction
Author(s) -
Ganesan Shanthi,
Summers Corey,
Pearce Sarah,
Gabler Nicholas,
Valentine Rudy,
Baumgard Lance,
Rhoads Robert,
Selsby Joshua
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.1290.6
Subject(s) - oxidative stress , malondialdehyde , superoxide dismutase , catalase , skeletal muscle , medicine , endocrinology , chemistry , reactive oxygen species , andrology , biology , biochemistry
Prolonged exposure to high temperatures can result in heat stress (HS), which is characterized by morbidities and mortality in humans and animals and appears to cause organ‐specific injury and dysfunction. We have previously found increased free radical injury in skeletal muscle following 24 hours of HS. The purpose of this investigation was to determine the extent to which short‐term HS caused muscle dysfunction in oxidative skeletal muscle. We hypothesized that in oxidative muscle 12 hours of HS would lead to free radical injury, apoptosis, autophagy, and decreased mitochondrial content compared to muscle from thermoneutral (TN) animals. To address this hypothesis, crossbred gilts (n=8/group) were assigned to three groups: TN (24° C), HS (37° C), or pair‐fed to heat stress (PFTN; 24° C) for 12 hours. Following treatment, animals were euthanized and the semitendinosus red (STR) was recovered. TN and PFTN were similar for nearly all measures indicating changes caused by HS were not due to reduced feed intake but due to the hyperthermic environment. The relative abundance of malondialdehyde modified proteins was increased by 36% in HS (p<0.05) compared to TN, which was matched by an inadequate antioxidant response including a 48% and 170% increase in superoxide dismutase (SOD) I and II relative protein abundance, respectively, and a 26% increase in total SOD activity but a 40% reduction in catalase activity in HS compared to TN. Further, HS caused a 103% increase in caspase 3 activation and tended to increase BCL2‐Associated X Protein by 40% (p<0.06) and apoptotic protease activating factor 1 by 66% (p<0.06) indicating increased apoptotic signaling. Despite increased initiation, autophagy appeared to be inhibited by HS as the microtubule‐associated protein A/B‐light chain 3 II/I ratio was decreased by 53% and sequestosome‐1(p62) protein abundance was increased by 40% in HS compared to TN. Markers of mitochondrial content cytochrome c, cytochrome c oxidase IV, voltage dependent anion channel, pyruvate dehydrogenase and prohibitins 1 were increased in HS compared to TN. Increased mitochondrial content is likely reflective of a combination of increased accumulation of damaged mitochondria that fail to be cleared via autophagy and mitochondrial biogenesis. We postulate that in oxidative skeletal muscle HS‐mediated mitochondrial dysfunction is allowed to persist due to a failure of autophagy to clear damaged mitochondria, which results in increased oxidative stress and apoptotic signaling. These data demonstrate widespread aberrant intracellular signaling caused by HS that implicate impaired autophagy as a key feature in HS‐mediated muscle dysfunction Support or Funding Information This work supported by USDA grants 2014‐67015‐21627 and 2011‐67003‐30007.