Despite well‐studied clinical manifestations, intracellular mechanisms of prolonged hyperthermic injury remain unclear, especially in skeletal muscle. Given muscle's large potential to impact systemic inflammation and metabolism, the response of muscle cells to heat‐mediated injury warrants further investigation. We have previously reported increased activation of NF‐κB signaling and increased NF‐κB and AP‐1‐driven transcripts in oxidative skeletal muscle following 12 h of heat stress. The purpose of this investigation was to examine early heat stress‐induced inflammatory signaling in skeletal muscle. We hypothesized that heat stress would increase NF‐κB and AP‐1 signaling in oxidative skeletal muscle. To address this hypothesis, 32 gilts were randomly assigned to one of four treatment groups (n = 8/group): control (0 h: 21°C) or exposed to heat stress conditions (37°C) for 2 h (n = 8), 4 h (n = 8), or 6 h (n = 8). Immediately following environmental exposure pigs were euthanized and the red portion of the semitendinosus muscle (STR) was harvested. We found evidence of NF‐κB pathway activation as indicated by increased protein abundance of NF‐κB activator IKK‐α following 4 h and increased total NF‐κB protein abundance following 6 h of heat stress. Heat stress also stimulated AP‐1 signaling as AP‐1 protein abundance was increased in nuclear fractions following 4 h of heat stress. Interleukin‐6 protein abundance and activation of the JAK/STAT pathway were decreased in heat stressed muscle. These data indicate that heat stress activated inflammatory signaling in the porcine STR muscle via the AP‐1 pathway and early activation of the NF‐κB pathway.

Heat stress contributes to higher morbidity and mortality in humans and animals and is an agricultural economic challenge because it reduces livestock productivity. Redox balance and associated mitochondrial responses appear to play a central role in heat stress‐induced skeletal muscle pathology. We have previously reported increased oxidative stress and mitochondrial content in oxidative muscle following 12 h of heat stress. The purposes of this investigation were to characterize heat stress‐induced oxidative stress and changes in mitochondrial content and biogenic signaling in oxidative skeletal muscle. Crossbred gilts were randomly assigned to either thermal neutral (21°C; n = 8, control group) or heat stress (37°C) conditions for 2 h (n = 8), 4 h (n = 8), or 6 h (n = 8). At the end, their respective environmental exposure, the red portion of the semitendinosus muscle (STR) was harvested. Heat stress increased concentration of malondialdehyde (MDA) following 2 and 4 h compared to thermal neutral and 6 h, which was similar to thermal neutral, and decreased linearly with time. Protein carbonyl content was not influenced by environment. Catalase activity was increased following 4 h of heat stress and superoxide dismutase activity was decreased following 6 h of heat stress compared to thermal neutral conditions. Heat stress‐mediated changes in antioxidant activity were independent of altered protein abundance or transcript expression. Mitochondrial content and mitochondrial biogenic signaling were similar between groups. These data demonstrate that heat stress caused a transient increase in oxidative stress that was countered by a compensatory change in catalase activity. These findings contribute to our growing understanding of the chronology of heat stress‐induced intracellular dysfunctions in skeletal muscle.

Highlights d HIV infection of hu-mice depletes pDC globally and impairs IFN-a production by pDC d DC expansion by Flt3L suppresses HIV infection in a pDCdependent manner d pDC from Flt3L-treated mice are more responsive to TLR7 stimulation d Early blocking of IFN-I signaling abolishes Flt3L-mediated suppression of viremia

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