Biology subjects

Graham, Z. A.

Publications and source records attributed to Graham, Z. A..

5 recordsLinked to original sources

bioRxiv2021

RNA-sequencing reveals a gene expression signature in skeletal muscle of a mouse model of age-associated post-operative functional decline

This study aimed to characterize the effects of laparotomy on post-operative physical function and skeletal muscle gene expression in C57BL/6N mice at 3, 20 and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre- and post-operative physical functioning were assessed by forelimb grip strength and motor coordination. Laparotomy induced an age-associated post-operative decline in forelimb grip strength that was greatest in the oldest mice. In contrast, while motor coordination declined with increasing age at baseline, it was unaffected by laparotomy. Moreover, baseline physical function as stratified by motor coordination performance (low vs. high functioning) in 24-month-old mice did not differentially affect post-laparotomy reduction in grip strength. RNA sequencing of soleus muscles showed that laparotomy induced age-associated differential gene expression and canonical pathway activation with the greatest effects in the youngest mice. Examples of such age-associated, metabolically important pathways that were only activated in the youngest mice after laparotomy included oxidative phosphorylation and NRF2-mediated oxidative stress response. Analysis of lipid mediators in serum and gastrocnemius muscle showed alterations in profiles of these mediators during aging and confirmed an association between such changes and functional status in gastrocnemius muscle. These findings demonstrate a mouse model of laparotomy which recapitulated some features of post-operative skeletal muscle decline in older adults following surgery, and identified age-associated, laparotomy-induced molecular signatures in skeletal muscles. Future research can build upon this mouse model to study molecular mechanisms of late-life vulnerability to acute surgical stress and resiliency to counter surgery-induced physical decline.

molecular biology↗

bioRxiv2021

Numb is required for optimal contraction of skeletal muscle

BackgroundThe role of Numb, a protein that is important for cell fate and development was investigated in adult skeletal muscle in mice using a conditional, inducible knockout (cKO) model. MethodsNumb expression was evaluated by Western blot. Numb localization was determined by confocal microscopy. The effects of cKO of Numb and the closely-related gene Numb-like in skeletal muscle fibers was evaluated by in-situ physiology; transmission and focused ion beam scanning electron microscopy; 3-dimensional reconstruction of mitochondrial; lipidomics; and bulk RNA-sequencing. Additional studies using primary mouse myotubes investigated the effects the effects of Numb knockdown on cell fusion, mitochondrial function and calcium transients. ResultsNumb protein expression was reduced by [~]70% (p < 0.01) at 24 as compared to 3 months of age. Numb was localized within muscle fibers as bands traversing fibers at regularly spaced intervals in close proximity to dihydropyridine receptors. The cKO of Numb and Numb-like reduced specific tetanic force by 36%, p < 0.01), altered mitochondrial spatial relationships to sarcomeric structures, increased Z-line spacing by 30% (p < 0.0001), perturbed sarcoplasmic reticulum organization and reduced mitochondrial volume by over 80% (p < 0.01). Only six genes were differentially expressed in cKO mice: Itga4, Sema7a, Irgm2, Vezf1, Mib1 and Tmem132a. Several lipid mediators derived from polyunsaturated fatty acid (PUFAs) through lipoxygenases were upregulated in Numb cKO skeletal muscle; 12-HEPE was increased by [~]250% (p < 0.05) and 17,18-EpETE by [~]240% (p < 0.05). In mouse primary myotubes, Numb knock-down reduced cell fusion ([~]20%, p < 0.01) and mitochondrial function and delayed the caffeine-induced rise in cytosolic calcium concentrations by more than 100% (p < 0.01). ConclusionsThese findings implicate Numb as a critical factor in skeletal muscle structure and function which appear to be critical for calcium release; we therefore speculate Numb plays critical roles in excitation-contraction coupling, one of the putative targets of aged skeletal muscles. These findings provide new insights into the molecular underpinnings of the loss of muscle function observed with sarcopenia.

physiology↗

bioRxiv2021

Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs its Signaling Pathways in Liver and Adipose Tissue in Mice

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and {beta}-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as {beta}-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPAR activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in shammice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulins action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

physiology↗

bioRxiv2020

Performance, but not size, of hindleg weaponry is sexually dimorphic in the giant mesquite bug (Thasus neocalifornicus)

In many species, males possess specialized weaponry that have evolved to confer a benefit during aggressive interactions. Because male weaponry is typically an exaggerated or extreme version of pre-existing body parts, females often possess reduced or weaponry. Although much research has investigated sexual dimorphism in the sizes of such weapons, other weapon components, such as weapon performance or alternative weapon forms can also explain the evolution of weapon sexual dimorphisms. Here, we investigated the allometry and variation of multiple weapon components of hindleg weaponry in the male and female giant mesquite bugs, Thasus necalifornicus. Despite theory predicating greater allocation in male weaponry, we found that females allocated more into the lengths of their hindlegs compared to males. Despite this allocation, males possess relatively wider hindlegs, which likely increase area of muscle mass. Indeed, the squeezing performance of male hindlegs was much greater than that of female hindlegs. Lastly, we also described the allometry and variation in a male weapon component, prominent tibial spines, which likely are used to damage competitors during aggressive interaction. Overall, our findings highlight the intricacies of weapon sexual dimorphism and demonstrate the importance of measuring multiple weapon components and not a single measure.

zoology↗

bioRxiv2020

Separating noise and function in systems of animal communication: a comparative study of aggressive signaling in crayfish

A primary issue in the study of dishonest signaling is the researchers ability to detect and describe a signal as being dishonest. However, by understanding the relative honesty of a signal as a statistical property of an individual or population, researchers have recently quantitively describe dishonest communication. Thus, dishonesty signals can be understood as when there is a breakdown in the correlation between a signal and its underlying meaning; creating variation within a signaling system. However, such variation in signaling systems may not be attributed to dishonesty, because of inherent noise within biological systems driven by evolutionary or physiological noise. Here, we try to separate out functional variation within honest or dishonesty signaling systems from inherent biological noise by leveraging homologous structures that have evolved for separate functions - the enlarged claws of freshwater crayfish. Because burrowing species of freshwater crayfish claws have not evolved as signals, the variability in the size and strength of their claws should be minimal when compared to claws of non-burrowing species that evolved as signals during aggression. We found that despite the claws of burrowing and nonburrowing crayfish claws having evolved to serve difference functions, the claws of all species in our study were inherently noisy. Furthermore, although claws that unreliably correlate to the strengthen the wielder may function as dishonest signals in other crustaceans, we did not find support for this hypothesis; because crayfish escalated aggression based on relative body size.

animal behavior and cognition↗