Search

© 2015 Güller et al.Background: In small mammals brown adipose tissue (BAT) plays a predominant role in regulating energy expenditure (EE) via adaptive thermogenesis. New-born babies require BAT to control their body temperature, however its relevance in a

Chronic complete spinal cord injury (SCI) is associated with severe skeletal muscle atrophy as well several atrophy and physical-inactivity-related comorbidity factors such as diabetes, obesity, lipid disorders, and cardiovascular diseases. Intracellular mechanisms associated with chronic complete SCI-related muscle atrophy are not well understood, and thus their characterization may assist with developing strategies to reduce the risk of comorbidity factors. Therefore, the aim of this study was to determine whether there was an increase in catabolic signaling targets, such as atrogin-1, muscle ring finger-1 (MuRF1), forkhead transcription factor (FoXO), and myostatin, and decreases in anabolic signaling targets, such as insulin-like growth factor (IGF), v-akt murine thymoma viral oncogene (Akt), glycogen synthase kinase-beta (GSK-3beta), mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and p70(s6kinase) in chronic complete SCI patients. In SCI patients, when compared with controls, there was a significant reduction in mRNA levels of atrogin-1 (59%; P < 0.05), MuRF1 (55%; P < 0.05), and myostatin (46%; P < 0.01), and in protein levels of FoXO1 (72%; P < 0.05), FoXO3a (60%; P < 0.05), and atrogin-1 (36%; P < 0.05). Decreases in the protein levels of IGF-1 (48%; P < 0.001) and phosphorylated GSK-3beta (54%; P < 0.05), 4E-BP1 (48%; P < 0.05), and p70(s6kinase) (60%; P = 0.1) were also observed, the latter three in an Akt- and mTOR-independent manner. Reductions in atrogin-1, MuRF1, FoXO, and myostatin suggest the existence of an internal mechanism aimed at reducing further loss of muscle proteins during chronic SCI. The downregulation of signaling proteins that regulate anabolism, such as IGF, GSK-3beta, and 4E-BP1, would reduce the ability to increase protein synthesis rates. [ABSTRACT FROM AUTHOR]

The mitochondrial DNA A3243G mutation causes neuromuscular disease. To investigate the muscle-specific pathophysiology of mitochondrial disease, rhabdomyosarcoma transmitochondrial hybrid cells (cybrids) were generated that retain the capacity to differentiate to myotubes. In some cases, striated muscle-like fibres were formed after innervation with rat embryonic spinal cord. Myotubes carrying A3243G mtDNA produced more reactive oxygen species than controls, and had altered glutathione homeostasis. Moreover, A3243G mutant myotubes showed evidence of abnormal mitochondrial distribution, which was associated with down-regulation of three genes involved in mitochondrial morphology, Mfn1, Mfn2 and DRP1. Electron microscopy revealed mitochondria with ultrastructural abnormalities and paracrystalline inclusions. All these features were ameliorated by anti-oxidant treatment, with the exception of the paracrystalline inclusions. These data suggest that rhabdomyosarcoma cybrids are a valid cellular model for studying muscle-specific features of mitochondrial disease and that excess reactive oxygen species production is a significant contributor to mitochondrial dysfunction, which is amenable to anti-oxidant therapy. [ABSTRACT FROM AUTHOR]

Extreme heterogeneity exists in the hypersensitive stress response exhibited by the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Because stress hypersensitivity can impact dystrophic phenotypes, this research aimed to understand the peripheral pathways driving this inter-individual variability. Male and female mdx mice were phenotypically stratified into "stress-resistant" or "stress-sensitive" groups based on their response to two laboratory stressors. Quantitative proteomics of striated muscle revealed that stress-resistant females were most dissimilar from all other groups, with over 250 proteins differentially regulated with stress hypersensitivity. Males showed less proteomic variation with stress hypersensitivity; however, these changes were associated with pathway enrichment. In the heart, stress-sensitive males had significant enrichment of pathways related to mitochondrial ATP synthesis, suggesting that increased cardio-metabolic capacity is associated with stress hypersensitivity in male mdx mice. In both sexes, stress hypersensitivity was associated with greater expression of beta-actin-like protein 2, indicative of altered cytoskeletal organisation. Despite identifying proteomic signatures associated with stress hypersensitivity, these did not correlate with differences in the serum metabolome acutely after a stressor. These data suggest that the heterogeneity in stress hypersensitivity in mdx mice is partially driven by cytoskeletal organisation, but that sex-specific cardio-metabolic reprogramming may also underpin this phenotype. SIGNIFICANCE: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease which is associated with a premature loss of ambulation and neurocognitive dysfunction. The hypersensitive stress response in DMD is a heterogeneous phenotype which is poorly understood. This study provided the first investigation of the peripheral mechanisms regulating the hypersensitive stress response by undertaking multi-omics analysis of phenotypically stratified mdx mice. Variations in behaviour and the striated muscle proteomic profiles suggest that cardio-metabolic remodelling and cytoskeletal organisation may contribute to this phenotype. This research offers significant insights into understanding how peripheral dystrophin deficiency relates to the cognitive abnormalities seen in patients with DMD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS. NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA-binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Trial Design: Older adults experience chronic dysregulation of leukocytes and inflammatory cytokines, both at rest and in response to resistance training. Systemic hypoxia modulates leukocytes and cytokines, therefore this study characterized the effects of normobaric hypoxia on the leukocyte and cytokine responses of older adults to resistance training., Methods: 20 adults aged 60-70 years performed eight weeks of moderate-intensity resistance training in either normoxia or normobaric hypoxia (14.4% O 2 ), consisting of two lower body and two upper body exercises. Venous blood was drawn before and after the training intervention and flow cytometry was used to quantify resting neutrophils, lymphocytes, monocytes, eosinophils and basophils, in addition to the subsets of lymphocytes (T, B and natural killer (NK) cells). Inflammatory cytokines were also quantified; interleukin 1 beta (IL-1β), IL-4, IL-6, IL-8, IL-10 and tumor necrosis factor alpha (TNF-α). Acute changes in leukocytes and cytokines were also measured in the 24 h following the last training session., Results: After the intervention there was a greater concentration of resting white blood cells (p = 0.03; 20.3% higher) T cells (p = 0.008; 25.4% higher), B cells (p = 0.004; 32.6% higher), NK cells (p = 0.012; 43.9% higher) and eosinophils (p = 0.025; 30.8% higher) in hypoxia compared to normoxia, though the cytokines were unchanged. No acute effect of hypoxia was detected in the 24 h following the last training session for any leukocyte population or inflammatory cytokine (p < 0.05)., Conclusions: Hypoxic training caused higher concentrations of resting lymphocytes and eosinophils, when compared to normoxic training. Hypoxia may have an additional beneficial effect on the immunological status of older adults., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR)., Trial Number: ACTRN12623001046695. Registered 27/9/2023. Retrospectively registered. All protocols adhere to the COSORT guidelines., (© 2024. The Author(s).)

Loss of function mutations in the gene encoding dystrophin elicits a hypersensitive fear response in mice and humans. In the dystrophin-deficient mdx mouse, this behaviour is partially protected by oestrogen, but the mechanistic basis for this protection is unknown. Here, we show that female mdx mice remain normotensive during restraint stress compared to a hypotensive and hypertensive response in male mdx and male/female wildtype mice, respectively. Partial dystrophin expression in female mdx mice (heterozygous) also elicited a hypertensive response. Ovariectomized (OVX) female mdx mice were used to explain the normotensive response to stress. OVX lowered skeletal muscle mass and lowered the adrenal mass and zona glomerulosa area (aldosterone synthesis) in female mdx mice. During a restraint stress, OVX dampened aldosterone synthesis and lowered the corticosterone:11-dehydrocorticosterone. All OVX-induced changes were restored with replacement of oestradiol, except that oestradiol lowered the zona fasciculata area of the adrenal gland, dampened corticosterone synthesis but increased cortisol synthesis. These data suggest that oestrogen partially attenuates the unconditioned fear response in mdx mice via adrenal and vascular function. It also suggests that partial dystrophin restoration in a dystrophin-deficient vertebrate is an effective approach to develop an appropriate hypertensive response to stress., (© 2023. The Author(s).)

Ageing causes a decline in leukocyte function and blunted leukocyte responses to resistance exercise. Systemic hypoxia exposure augments the leukocyte response to resistance exercise in young adults, yet this response remains uncharacterised in older adults. This study characterised the effects of normobaric hypoxia on the acute leukocyte and inflammatory cytokine responses to resistance exercise in older adults. We recruited 20 adults aged 60-70 years to perform an acute bout of resistance exercise in normobaric hypoxia (FiO 2 14.4%; n = 10) or normoxia (FiO 2 20.93%; n = 10). Participants completed 4 × 10 repetitions of lower and upper body exercises at 70% of their predicted 1-repetition maximum. Venous blood was sampled before and up to 24 hours post-exercise to quantify neutrophils, lymphocytes, monocytes, eosinophils, basophils and cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, TNFα). Flow cytometry was used to classify lymphocytes as T (CD4 + helper and CD8 + cytotoxic), B and NK cells, in addition to the expression of the senescence marker CD45RA on T cells. The hypoxic group showed a larger lymphocyte response over the 24 hours post-exercise compared to the normoxic group (p = 0.035). Specifically, there were greater concentrations of CD4 + T helper cells following hypoxic exercise compared to normoxia (p = 0.046). There was also a greater proportion of CD45RA + CD4 + T helper cells, suggesting that the cells were more senescent (p = 0.044). Hypoxia did not impact any other leukocyte population or cytokine following exercise. Normobaric hypoxia increases the lymphocyte response to an acute bout of resistance exercise in older adults., Competing Interests: The authors declare no conflict of interest., (Copyright © Biology of Sport 2023.)

Claws are a common anatomical feature among limbed amniotes and contribute to a variety of functions including prey capture, locomotion, and attachment. Previous studies of both avian and non-avian reptiles have found correlations between habitat use and claw morphology, suggesting that variation in claw shape permits effective functioning in different microhabitats. How, or if, claw morphology influences attachment performance, particularly in isolation from the rest of the digit, has received little attention. To examine the effects of claw shape on frictional interactions, we isolated the claws of preserved specimens of Cuban knight anoles (Anolis equestris), quantified variation in claw morphology via geometric morphometrics, and measured friction on four different substrates that varied in surface roughness. We found that multiple aspects of claw shape influence frictional interactions, but only on substrates for which asperities are large enough to permit mechanical interlocking with the claw. On such substrates, the diameter of the claw's tip is the most important predictor of friction, with narrower claw tips inducing greater frictional interactions than wider ones. We also found that claw curvature, length, and depth influence friction, but that these relationships depend on the substrate's surface roughness. Our findings suggest that although claw shape plays a critical role in the effective clinging ability of lizards, its relative importance is dependent upon the substrate. Description of mechanical function, as well as ecological function, is critical for a holistic understanding of claw shape variation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective: Skeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function., Methods: We assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity., Results: ERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis., Conclusions: Our findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Dermatographism was first described by William Heberden (1710-1801) more than 250 years ago as a type of urticaria brought on by rubbing or scratching the skin. In 1859, William Gull (1816-1890) gave it the name factitious urticaria, distinguishing dermatographism from chronic urticaria, in which the skin lesions appear spontaneously. During the 1870s French physicians at the Salpetriere Hospital in Paris became impressed by their ability to write words on the bodies of patients admitted with hysteria and other psychiatric disorders, who also exhibited dermatographism. At first, they described this phenomenon as "autographisme," but by 1890 it became known as "dermographisme," the forerunner of the current term "dermatographism." At the Salpetriere and elsewhere in the world, it became fashionable to photograph patients with dermatographism, to capture the striking urticarial writing on their skin. These photographs were used in atlases and to illustrate dermatology texts and medical journals as well as popular magazines. This contribution presents several vintage photographs of dermatographism from the late 19th century to the early 20th century. Dermatographism has also become featured in popular culture including film, comic books, poetry, and body art, examples of which are provided in this contribution with the assistance of two of our authors, Ariana Page Russell and Jeannine Hall Gailey, who have embraced their dermatographism and have used their artistic and poetic talents to educate and inspire patients about this common skin condition., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Gekkotan lizards of the genus Hemidactylus exhibit derived digital morphologies. These include heavily reduced antepenultimate phalanges of digits III and IV of the manus and digits III-V of the pes, as well as enigmatic cartilaginous structures called paraphalanges. Despite this well-known morphological derivation, no studies have investigated the development of these structures. We aimed to determine if heterochrony underlies the derived antepenultimate phalanges of Hemidactylus. Furthermore, we aimed to determine if convergently evolved paraphalanges exhibit similar or divergent developmental patterns. Herein we describe embryonic skeletal development in the hands and feet of four gekkonid species, exhibiting a range of digital morphologies. We determined that the derived antepenultimate phalanges of Hemidactylus are the products of paedomorphosis. Furthermore, we found divergent developmental patterns between convergently evolved paraphalanges., (© 2022 Anatomical Society.)

Abstract: Allsopp, GL, Hoffmann, SM, Feros, SA, Pasco, JA, Russell, AP, and Wright, CR. The effect of normobaric hypoxia on resistance training adaptations in older adults. J Strength Cond Res 36(8): 2306-2312, 2022-The effect of normobaric hypoxia on strength, body composition, and cardiovascular fitness was investigated after a resistance training intervention in older adults. A single-blinded, randomized control trial recruited 20 healthy adults aged 60-75 years for an 8-week resistance training intervention in normoxia ( n = 10) or normobaric hypoxia (14.4% O 2 ; n = 10). Subjects performed 2 sessions per week of upper-body and lower-body exercises at 70% of 1 repetition maximum (1RM). Pretraining and post-training, maximal oxygen uptake (V̇O 2 max), muscular endurance (30 maximal knee flexions/extensions), and 5RM were assessed, with 5RM used to calculate 1RM. Subjects underwent whole-body dual-energy x-ray absorptiometry (DXA) at pretraining and post-training for fat and lean mass quantification. Significance was set at p < 0.05. Subjects in both groups substantially improved their calculated 1RM strength for leg extension, pectoral fly, row, and squat (normoxia; 30, 38, 27, and 29%, hypoxia; 43, 50, 28, and 64%, respectively); however, hypoxia did not augment this response. Hypoxia did not enhance V̇O 2 max or muscular endurance responses after the training intervention, with no improvements seen in either group. Fat mass and lean mass remained unchanged in both groups after the intervention. In summary, 8 weeks of resistance training in hypoxia was well tolerated in healthy older adults and increased upper-body and lower-body strength. However, the magnitude of strength and lean muscle improvements in hypoxia was no greater than normoxia; therefore, there is currently no evidence to support the use of hypoxic resistance training in older adults., (Copyright © 2020 National Strength and Conditioning Association.)

Purpose: In young adults, the hormonal responses to resistance exercise are amplified by normobaric hypoxia. Hormone concentrations and metabolism are typically dysregulated with age, yet the impact of hypoxia on these responses to resistance exercise are uncharacterised. Therefore, this study aimed to characterise the acute and chronic hormonal and metabolic responses of older adults to resistance training in normobaric hypoxia., Methods: Adults aged 60-75 years completed 8 weeks of resistance training in either normoxia (20.9% O 2 ; n = 10) or normobaric hypoxia (14.4% O 2 , n = 10) twice weekly at 70% of their predicted 1-repetition maximum. Growth hormone, glucose, lactate, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), cortisol, total testosterone, adrenaline, noradrenaline and dopamine were quantified at pre- and post-training, and in the 60 min following the first training session (untrained state) and the last training session (trained state)., Results: Eight weeks of training in hypoxia did not affect the resting levels of the hormones or physiological factors measured. However, hypoxia significantly blunted the acute growth hormone response in the 15 min following the last training session at week eight (43.87% lower in the hypoxic group; p = 0.017). This novel and unexpected finding requires further investigation. All other hormones were unaffected acutely by hypoxia in the 60 min following the first and the last training session., Conclusion: Chronic resistance training in normobaric hypoxia supresses the growth hormone response to exercise in older adults. All other hormones and metabolic markers were unaffected both acutely and chronically by hypoxia., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Resistance-based blood flow restriction training (BFRT) improves skeletal muscle strength and size. Unlike heavy-load resistance training (HLRT), there is debate as to whether strength adaptations following BFRT interventions can be primarily attributed to concurrent muscle hypertrophy, as the magnitude of hypertrophy is often minor. The present study aimed to investigate the effect of 7 weeks of BFRT and HLRT on muscle strength and hypertrophy. The expression of protein growth markers from muscle biopsy samples was also measured. Male participants were allocated to moderately heavy-load training (HL; n  = 9), low-load BFRT (LL + BFR; n  = 8), or a control (CON; n  = 9) group to control for the effect of time. HL and LL + BFR completed 21 training sessions (3 d.week -1 ) comprising bilateral knee extension and knee flexion exercises (HL = 70% one-repetition maximum (1-RM), LL + BFR = 20% 1-RM + blood flow restriction). Bilateral knee extension and flexion 1-RM strength were assessed, and leg muscle CSA was measured via peripheral quantitative computed tomography. Protein growth markers were measured in vastus lateralis biopsy samples taken pre- and post the first and last training sessions. Biopsy samples were also taken from CON at the same time intervals as HL and LL + BFR. Knee extension 1-RM strength increased in HL (19%) and LL + BFR (19%) but not CON (2%; p  < 0.05). Knee flexion 1-RM strength increased similarly between all groups, as did muscle CSA (50% femur length; HL = 2.2%, LL + BFR = 3.0%, CON = 2.1%; TIME main effects). 4E-BP1 (Thr37/46) phosphorylation was lower in HL and LL + BFR immediately post-exercise compared with CON in both sessions ( p  < 0.05). Expression of other growth markers was similar between groups ( p  > 0.05). Overall, BFRT and HLRT improved muscle strength and size similarly, with comparable changes in intramuscular protein growth marker expression, both acutely and chronically, suggesting the activation of similar anabolic pathways. However, the low magnitude of muscle hypertrophy was not significantly different to the non-training control suggesting that strength adaptation following 7 weeks of BFRT is not driven by hypertrophy, but rather neurological adaptation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 May, Russell, Della Gatta and Warmington.)

Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained β-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ β-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutation to the gene encoding dystrophin can cause Duchenne muscular dystrophy (DMD) and increase the sensitivity to stress in vertebrate species, including the mdx mouse model of DMD. Behavioral stressors can exacerbate some dystrophinopathy phenotypes of mdx skeletal muscle and cause hypotension-induced death. However, we have discovered that a subpopulation of mdx mice present with a wildtype-like response to mild (forced downhill treadmill exercise) and moderate (scruff restraint) behavioral stressors. These "stress-resistant" mdx mice are more physically active, capable of super-activating the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone pathways following behavioral stress and they express greater levels of mineralocorticoid and glucocorticoid receptors in striated muscle relative to "stress-sensitive" mdx mice. Stress-resistant mdx mice also presented with a less severe striated muscle histopathology and greater exercise and skeletal muscle oxidative capacity at rest. Most interestingly, female mdx mice were more physically active following behavioral stressors compared to male mdx mice; a response abolished after ovariectomy and rescued with estradiol. We demonstrate that the response to behavioral stress greatly impacts disease severity in mdx mice suggesting the management of stress in patients with DMD be considered as a therapeutic approach to ameliorate disease progression., (© 2021 Federation of American Societies for Experimental Biology.)

The remarkable ability of geckos to adhere to smooth surfaces is often thought of in terms of external structures, including the branching setae that make contact with the surface producing van der Waals forces. Some geckos also exhibit unique movements of the distal segments of the limbs during locomotion and static clinging, including active digital hyperextension and considerable pedal rotation. During static clinging, geckos can exhibit considerable adduction/abduction of the pes while the crus and thigh remain firmly adpressed to the substratum. This decoupling of pedal adduction/abduction from ankle flexion/extension and pedal long-axis rotation is a significant departure from pedal displacements of a typical lizard lacking adhesive ability. The structure of the ankle is likely key to this decoupling, although no detailed comparison of this complex joint between pad-bearing geckos and other lizards is available. Here we compare the configuration of the mesotarsal joint of nongekkotan lizards (Iguana and Pristidactylus) with that of the Tokay gecko (Gekko gecko) using prepared skeletons, scanning electron microscopy, and micro-computed tomographic (µCT) scans. We focus on the structure of the astragalocalcaneum and the fourth distal tarsal. The mesotarsal joint exhibits a suite of modifications that are likely associated with the secondarily symmetrical pes of pad-bearing geckos. For example, the lateral process of the astragalocalcaneum is much more extensive in G. gecko compared with other lizards. The mesotarsal joint exhibits several other differences permitting dissociation of long-axis rotation of the pes from flexion-extension movement, including a reduced ventral peg on the fourth distal tarsal, an articulatory pattern dominated by a well-defined, expansive distomesial notch of the astragalocalcaneum, and an associated broad proximodorsal articulatory facet of the fourth distal tarsal. Pad-bearing geckos are capable of effectively deploying their intricate adhesive system across a broad array of body angles because of this highly modified ankle. Future research should determine whether the differences encountered in G. gecko (and their extent) apply to the Gekkota as a whole and should examine how the elements of the ankle move dynamically during locomotion across a range of taxa., (© 2021 Anatomical Society.)