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1. Acute phase response to exertional heat stroke in mice

   https://doi.org/10.1113/EP088501  

   Iwaniec, John ; Robinson, Gerard P. ; Garcia, Christian K. ; Murray, Kevin O. ; de Carvalho, Lucas ; Clanton, Thomas L. ; Laitano, Orlando ( May 2020 , Experimental Physiology)

   What is the central question of this study?

   Exertional heat stroke is accompanied by a marked inflammatory response. In this study, we explored the time course of acute phase proteins during recovery from severe heat stress in mice and the potential role of skeletal muscles as their source.

   What is the main finding and its importance?

   Exertional heat stroke transiently increased expression of acute phase proteins in mouse liver and plasma and depleted liver and plasma fibrinogen, a typical response to severe trauma. In contrast, skeletal muscle fibrinogen production was stimulated by heat stroke, which can provide an additional reservoir for fibrinogen supply to maintain the clotting potential throughout the body and locally within the muscle.

   Exertional heat stroke (EHS), the most severe manifestation of heat illness, is accompanied by a marked inflammatory response. The release of acute phase proteins (APPs) is an important component of inflammation, which can assist in tissue survival/repair. The time course of APPs in recovery from EHS is unknown. Furthermore, skeletal muscles produce APPs during infection, but it is unknown whether they can produce APPs after EHS. Our objective was to determine the time course of representative APPs in liver, plasma and skeletal muscle during recovery from EHS. Male C57BL6/J mice ran in a forced running wheel at 37.5°C, 40% relative humidity until symptom limitation. Exercise control (EXC) mice ran for the same duration and intensity at 22.5°C. Samples were collected (n = 6–12 per group) over 14 days of recovery. Protein abundance was quantified using immunoblots. Total and phosphorylated STAT3 (pSTAT3) at Tyr705, responsible for APP activation, increased in liver at 0.5 h after EHS compared with EXC, (P < 0.05 andP < 0.001, respectively). In contrast, in tibialis anterior (TA) muscle, total STAT3 increased at 3 h (P < 0.05) but pSTAT3 (Tyr705) did not. Liver serum amyloid A1 (SAA1) increased at 3 and 24 h after EHS (P < 0.05), whereas plasma SAA1 increased only at 3 h (P < 0.05). SAA1 was not detected in TA muscle. In liver and plasma, fibrinogen decreased at 3 h (P < 0.01) and increased in TA muscle (P < 0.05). Lipocalin‐2 was undetectable in liver or TA muscle. Recovery from EHS is characterized by a transient acute phase response in both liver and skeletal muscle. However, APP expression profiles and subtypes differ between skeletal muscle and liver.

    

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2. The effect of lifelong endurance exercise on cardiovascular structure and exercise function in women

   https://doi.org/10.1113/JP278503  

   Carrick‐Ranson, Graeme ; Sloane, Nikita M. ; Howden, Erin J. ; Bhella, Paul S. ; Sarma, Satyam ; Shibata, Shigeki ; Fujimoto, Naoki ; Hastings, Jeffrey L. ; Levine, Benjamin D. ( May 2020 , The Journal of Physiology)

   The beneficial effects of sustained or lifelong (>25 years) endurance exercise on cardiovascular structure and exercise function have been largely established in men.

   The current findings indicate that committed (≥4 weekly exercise sessions) lifelong exercise results in substantial benefits in exercise capacity (), cardiovascular function at submaximal and maximal exercise, left ventricular mass and compliance, and blood volume compared to similarly aged or even younger (middle‐age) untrained women.

   Endurance exercise training should be considered a key strategy to prevent cardiovascular disease with ageing in women as well as men.

   This study was a retrospective, cross‐sectional analysis of exercise performance and left ventricular (LV) morphology in 70 women to examine whether women who have performed regular, lifelong endurance exercise acquire the same beneficial adaptations in cardiovascular structure and function and exercise performance that have been reported previously in men. Three groups of women were examined: (1) 35 older (>60 years) untrained women (older untrained, OU), (2) 13 older women who had consistently performed four or more endurance exercise sessions weekly for at least 25 years (older trained, OT), and (3) 22 middle‐aged (range 35–59 years) untrained women (middle‐aged untrained, MU) as a reference control for the appropriate age‐related changes. Oxygen uptake () and cardiovascular function (cardiac output (); stroke volume (SV) acetylene rebreathing) were examined at rest, steady‐state submaximal exercise and maximal exercise (maximal oxygen uptake,). Blood volume (CO rebreathing) and LV mass (cardiac magnetic resonance imaging), plus invasive measures of static and dynamic chamber compliance were also examined.(p < 0.001) and maximal exerciseand SV were larger in older trained women compared to the two untrained groups (∼17% and ∼27% forand SV, respectively,versusMU; ∼40% and ∼38%versusOU, allp < 0.001). Blood volume (mL kg⁻¹) and LV mass index (g m⁻²) were larger in OTversusOU (∼11% and ∼16%, respectively, bothP ≤ 0.015) Static LV chamber compliance was greater in OT compared to both untrained groups (median (25–75%): MU: 0.065 (0.049–0.080); OU: 0.085 (0.061–0.138); OT: 0.047 (0.031–0.054),P ≤ 0.053). Collectively, these findings indicate that lifetime endurance exercise appears to be extremely effective at preserving or even enhancing cardiovascular structure and function with advanced age in women.

    

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3. No effect of endoperoxide 4 or thromboxane A 2 receptor blockade on static mechanoreflex activation in rats with heart failure

   https://doi.org/10.1113/EP088835  

   Butenas, Alec L. E. ; Rollins, Korynne S. ; Matney, Jacob E. ; Williams, Auni C. ; Kleweno, Talyn E. ; Parr, Shannon K. ; Hammond, Stephen T. ; Ade, Carl J. ; Hageman, Karen S. ; Musch, Timothy I. ; et al ( October 2020 , Experimental Physiology)

   What is the central question of this study?

   Do endoperoxide 4 and thromboxane A₂receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF‐rEF)?

   What is the main finding and its importance?

   The data do not support a role for endoperoxide 4 receptors or thromboxane A₂receptors in the chronic mechanoreflex sensitization in HF‐rEF rats.

   We investigated the role of cyclooxygenase metabolite‐associated endoperoxide 4 receptors (EP4‐R) and thromboxane A₂receptors (TxA₂‐R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction‐induced heart failure with reduced ejection fraction (HF‐rEF). We hypothesized that injection of either the EP4‐R antagonist L‐161,982 (1 µg) or the TxA₂‐R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF‐rEF rats but not sham‐operated control rats (SHAM). Ejection fraction was significantly reduced in HF‐rEF (45 ± 11%) compared to SHAM (83 ± 6%;P < 0.01) rats. In SHAM and HF‐rEF rats, we found that the EP4‐R antagonist had no effect on the peak increase in mean arterial pressure (peak ΔMAP SHAMn = 6, pre: 15 ± 7, post: 15 ± 9,P = 0.99; HF‐rEFn = 9, pre: 30 ± 11, post: 32 ± 15 mmHg,P = 0.84) or peak increase in RSNA (peak ΔRSNA SHAM pre: 33 ± 14, post: 47 ± 31%,P = 0.94; HF‐rEF, pre: 109 ± 47, post: 139 ± 150%,P = 0.76) response to stretch. Similarly, in SHAM and HF‐rEF rats, we found that the TxA₂‐R antagonist had no effect on the peak ΔMAP (SHAMn = 7, pre: 13 ± 7, post: 19 ± 14,P = 0.15; HF‐rEFn = 14, pre: 24 ± 13, post: 21 ± 13 mmHg,P = 0.47) or peak ΔRSNA (SHAM pre: 52 ± 43, post: 57 ± 67%,P = 0.94; HF‐rEF, pre: 108 ± 93, post: 88 ± 72%,P = 0.30) response to stretch. The data do not support a role for EP4‐Rs or TxA₂‐Rs in the chronic mechanoreflex sensitization in HF‐rEF.

    

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4. Deletion of Fibroblast growth factor 9 globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments

   https://doi.org/10.1002/dvdy.383  

   Leek, Connor C. ; Soulas, Jaclyn M. ; Bhattacharya, Iman ; Ganji, Elahe ; Locke, Ryan C. ; Smith, Megan C. ; Bhavsar, Jaysheel D. ; Polson, Shawn W. ; Ornitz, David M. ; Killian, Megan L. ( June 2021 , Developmental Dynamics)

   The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon‐bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion offibroblast growth factor 9(Fgf9), the DT size is notably enlarged. In this study, we explored the tissue‐specific regulation of DT size using both global and targeted deletion ofFgf9.

   We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss ofFgf9. Loss ofFgf9during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development inFgf9^nullattachments. We then showed that targeted deletion ofFgf9in skeletal muscle leads to postnatal enlargement of the DT.

   Taken together, we discovered thatFgf9may play an influential role in muscle‐bone cross‐talk during embryonic and postnatal development.

    

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5. Chronic cold exposure induces mitochondrial plasticity in deer mice native to high altitudes

   https://doi.org/10.1113/JP280298  

   Mahalingam, Sajeni ; Cheviron, Zachary A. ; Storz, Jay F. ; McClelland, Grant B. ; Scott, Graham R. ( September 2020 , The Journal of Physiology)

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in cold hypoxic environments remains unresolved.

   We examined high‐altitude deer mice, which have evolved a high capacity for aerobic thermogenesis, to determine the mechanisms of mitochondrial plasticity during chronic exposure to cold and hypoxia, alone and in combination.

   Cold exposure in normoxia or hypoxia increased mitochondrial leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency, which may serve to augment non‐shivering thermogenesis. Cold also increased muscle oxidative capacity, but reduced the capacity for mitochondrial respiration via complex II relative to complexes I and II combined.

   High‐altitude mice had a more oxidative muscle phenotype than low‐altitude mice.

   Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitude.

   Small mammals native to high altitude must sustain high rates of thermogenesis to cope with cold and hypoxic environments. Skeletal muscle is a key site of shivering and non‐shivering thermogenesis, but the importance of mitochondrial plasticity in small mammals at high altitude remains unresolved. High‐altitude deer mice (Peromyscus maniculatus) and low‐altitude white‐footed mice (P. leucopus) were born and raised in captivity, and chronically exposed as adults to warm (25°C) normoxia, warm hypoxia (12 kPa O₂), cold (5°C) normoxia, or cold hypoxia. We then measured oxidative enzyme activities, oxidative fibre density and capillarity in the gastrocnemius, and used a comprehensive substrate titration protocol to examine the function of muscle mitochondria by high‐resolution respirometry. Exposure to cold in both normoxia or hypoxia increased the activities of citrate synthase and cytochrome oxidase. In lowlanders, this was associated with increases in capillary density and the proportional abundance of oxidative muscle fibres, but in highlanders, these traits were unchanged at high levels across environments. Environment had some distinct effects on mitochondrial OXPHOS capacity between species, but the capacity of complex II relative to the combined capacity of complexes I and II was consistently reduced in both cold environments. Both cold environments also increased leak respiration and decreased phosphorylation efficiency and OXPHOS coupling efficiency in both species, which may serve to augment non‐shivering thermogenesis. These cold‐induced changes in mitochondrial function were overlaid upon the generally more oxidative phenotype of highlanders. Therefore, both plasticity and evolved changes in muscle mitochondria contribute to thermogenesis at high altitudes.

    

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