skip to main content

Title: Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle
New Findings

What is the central question of this study?

The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload?

What is the main finding and its importance?

Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus.


Divergent skeletal muscle phenotypes result from chronic resistance‐type versus endurance‐type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT;n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non‐overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. −6 ± 18%, mean ± SD,< 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, = 0.015). Between‐group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload.In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

more » « less
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
Date Published:
Journal Name:
Experimental Physiology
Page Range / eLocation ID:
p. 714-725
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. New Findings

    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.

    more » « less
  2. Key points

    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.

    more » « less
  3. New Findings

    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 SHAM= 6, pre: 15 ± 7, post: 15 ± 9,P = 0.99; HF‐rEF= 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 (SHAM= 7, pre: 13 ± 7, post: 19 ± 14,P = 0.15; HF‐rEF= 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.

    more » « less
  4. Abstract Background

    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 inFgf9nullattachments. 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.

    more » « less
  5. Key points

    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.

    more » « less