̽��ֱ�� of Cambridge - Eugene Terentjev

Mathematical model predicts best way to build muscle

sc604 — Mon, 23 Aug 2021 04:28:37 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, used methods of theoretical biophysics to construct the model, which can tell how much a specific amount of exertion will cause a muscle to grow and how long it will take. ̽��ֱ��model could form the basis of a software product, where users could optimise their exercise regimes by entering a few details of their individual physiology.

̽��ֱ��model is based on earlier work by the same team, which found that a component of muscle called titin is responsible for generating the chemical signals which affect muscle growth.

̽��ֱ��results, reported in the Biophysical Journal, suggest that there is an optimal weight at which to do resistance training for each person and each muscle growth target. Muscles can only be near their maximal load for a very short time, and it is the load integrated over time which activates the cell signalling pathway that leads to synthesis of new muscle proteins. But below a certain value, the load is insufficient to cause much signalling, and exercise time would have to increase exponentially to compensate. ̽��ֱ��value of this critical load is likely to depend on the particular physiology of the individual.

We all know that exercise builds muscle. Or do we? “Surprisingly, not very much is known about why or how exercise builds muscles: there’s a lot of anecdotal knowledge and acquired wisdom, but very little in the way of hard or proven data,” said Professor Eugene Terentjev from Cambridge’s Cavendish Laboratory, one of the paper’s authors.

When exercising, the higher the load, the more repetitions or the greater the frequency, then the greater the increase in muscle size. However, even when looking at the whole muscle, why or how much this happens isn’t known. ̽��ֱ��answers to both questions get even trickier as the focus goes down to a single muscle or its individual fibres.

Muscles are made up of individual filaments, which are only 2 micrometres long and less than a micrometre across, smaller than the size of the muscle cell. “Because of this, part of the explanation for muscle growth must be at the molecular scale,” said co-author Neil Ibata. “ ̽��ֱ��interactions between the main structural molecules in muscle were only pieced together around 50 years ago. How the smaller, accessory proteins fit into the picture is still not fully clear.”

This is because the data is very difficult to obtain: people differ greatly in their physiology and behaviour, making it almost impossible to conduct a controlled experiment on muscle size changes in a real person. “You can extract muscle cells and look at those individually, but that then ignores other problems like oxygen and glucose levels during exercise,” said Terentjev. “It’s very hard to look at it all together.”

Terentjev and his colleagues started looking at the mechanisms of mechanosensing – the ability of cells to sense mechanical cues in their environment – several years ago. ̽��ֱ��research was noticed by the English Institute of Sport, who were interested in whether it might relate to their observations in muscle rehabilitation. Together, they found that muscle hyper/atrophy was directly linked to the Cambridge work.

In 2018, the Cambridge researchers started a project on how the proteins in muscle filaments change under force. They found that main muscle constituents, actin and myosin, lack binding sites for signalling molecules, so it had to be the third-most abundant muscle component – titin – that was responsible for signalling the changes in applied force.

Whenever part of a molecule is under tension for a sufficiently long time, it toggles into a different state, exposing a previously hidden region. If this region can then bind to a small molecule involved in cell signalling, it activates that molecule, generating a chemical signal chain. Titin is a giant protein, a large part of which is extended when a muscle is stretched, but a small part of the molecule is also under tension during muscle contraction. This part of titin contains the so-called titin kinase domain, which is the one that generates the chemical signal that affects muscle growth.

̽��ֱ��molecule will be more likely to open if it is under more force, or when kept under the same force for longer. Both conditions will increase the number of activated signalling molecules. These molecules then induce the synthesis of more messenger RNA, leading to production of new muscle proteins, and the cross-section of the muscle cell increases.

This realisation led to the current work, started by Ibata, himself a keen athlete. “I was excited to gain a better understanding of both the why and how of muscle growth,” he said. “So much time and resources could be saved in avoiding low-productivity exercise regimes, and maximising athletes’ potential with regular higher value sessions, given a specific volume that the athlete is capable of achieving.”

Terentjev and Ibata set out to constrict a mathematical model that could give quantitative predictions on muscle growth. They started with a simple model that kept track of titin molecules opening under force and starting the signalling cascade. They used microscopy data to determine the force-dependent probability that a titin kinase unit would open or close under force and activate a signalling molecule.

They then made the model more complex by including additional information, such as metabolic energy exchange, as well as repetition length and recovery. ̽��ֱ��model was validated using past long-term studies on muscle hypertrophy.

“While there is experimental data showing similar muscle growth with loads as little as 30% of maximum load, our model suggests that loads of 70% are a more efficient method of stimulating growth,” said Terentjev, who is a Fellow of Queens' College. “Below that, the opening rate of titin kinase drops precipitously and precludes mechanosensitive signalling from taking place. Above that, rapid exhaustion prevents a good outcome, which our model has quantitatively predicted.”

“One of the challenges in preparing elite athletes is the common requirement for maximising adaptations while balancing associated trade-offs like energy costs,” said Fionn MacPartlin, Senior Strength & Conditioning Coach at the English Institute of Sport. “This work gives us more insight into the potential mechanisms of how muscles sense and respond to load, which can help us more specifically design interventions to meet these goals.”

̽��ֱ��model also addresses the problem of muscle atrophy, which occurs during long periods of bed rest or for astronauts in microgravity, showing both how long can a muscle afford to remain inactive before starting to deteriorate, and what the optimal recovery regime could be.

Eventually, the researchers hope to produce a user-friendly software-based application that could give individualised exercise regimes for specific goals. ̽��ֱ��researchers also hope to improve their model by extending their analysis with detailed data for both men and women, as many exercise studies are heavily biased towards male athletes.

Reference:
Neil Ibata and Eugene M. Terentjev. ‘Why exercise builds muscles: Titin mechanosensing controls skeletal muscle growth under load.’ Biophysical Journal (2021). DOI: 10.1016/j.bpj.2021.07.023

Researchers have developed a mathematical model that can predict the optimum exercise regime for building muscle.

Surprisingly, not very much is known about why or how exercise builds muscles: there’s a lot of anecdotal knowledge and acquired wisdom, but very little in the way of hard or proven data

Eugene Terentjev

John Arano on Unsplash

Woman lifting weights

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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New method developed for ‘up-sizing’ mini organs used in medical research

sc604 — Mon, 08 Feb 2021 17:16:20 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, used their method to culture and grow a ‘mini-airway’, the first time that a tube-shaped organoid has been developed without the need for any external support.

Using a mould made of a specialised polymer, the researchers were able to guide the size and shape of the mini-airway, grown from adult mouse stem cells, and then remove it from the mould when it reached the point where it could support itself.

Whereas the organoids currently used in medical research are at the microscopic scale, the method developed by the Cambridge team could make it possible to grow life-sized versions of organs. Their results are reported in the journal Advanced Science.

Organoids are tiny, three-dimensional cell assemblies that mimic the cell arrangement of fully-grown organs. They can be a useful way to study human biology and how it can go wrong in various diseases, and possibly how to develop personalised or regenerative treatments. However, assembling them into larger organ structures remains a challenge.

Other research teams have experimented with 3D printing techniques to develop larger mini-organs, but these often require an external support structure.

“Mini-organs are very small and highly fragile,” said Dr Yan Yan Shery Huang from Cambridge’s Department of Engineering, who co-led the research. “In order to scale them up, which would increase their usefulness in medical research, we need to find the right conditions to help the cells self-organise.”

Huang and her colleagues have proposed a new organoid engineering approach called Multi-Organoid Patterning and Fusion (MOrPF) to grow a miniature version of a mouse airway using stem cells. Using this technique, the scientists achieved faster assembly of organoids into airway tubes with uninterrupted passageways. ̽��ֱ��mini-airways grown using the MOrPF technique showed potential for scaling up to match living organ structures in size and shape, and retained their shape even in the absence of an external support.

̽��ֱ��MOrPF technique involves several steps. First, a polymer mould – like a miniature version of a cake or jelly mould – is used to shape a cluster of many small organoids. ̽��ֱ��cluster is released from the mould after one day, and then grown for a further two weeks. ̽��ֱ��cluster becomes one single tubular structure, covered by an outer layer of airway cells. ̽��ֱ��moulding process is just long enough for the outer layer of the cells to form an envelope around the entire cluster. During the two weeks of further growth, the inner walls gradually disappear, leading to a hollow tubular structure.

“Gradual maturation of the cells is really important,” said Dr Joo-Hyeon Lee from Cambridge’s Wellcome – MRC Cambridge Stem Cell Institute, who co-led the research. “ ̽��ֱ��cells need to be well-organised before we can release them so that the structures don’t collapse.”

̽��ֱ��organoid cluster can be thought of like soap bubbles, initially packed together to form to the shape of the mould. In order to fuse into a single gigantic bubble from the cluster of compressed bubbles, the inner walls need to be broken down. In the MOrPF process, the fused organoid clusters are released from the mould to grow in floating, scaffold-free conditions, so that the cells forming the inner walls of the fused cluster can be taken out of the cluster. ̽��ֱ��mould can be made into different sizes or shapes, so that the researchers can pre-determine the shape of the finished mini-organ.

“ ̽��ֱ��interesting thing is, if you think about the soap bubbles, the resulting big bubble is always spherical, but the special mechanical properties of the cell membrane of organoids make the resulting fused shape preserve the shape of the mould,” said co-author Professor Eugene Terentjev from Cambridge’s Cavendish Laboratory.

̽��ֱ��team say their method closely approximated the natural process of organ tube formation in some animal species. They are hopeful that their technique will help create biomimetic organs to facilitate medical research.

̽��ֱ��researchers first plan to use their method to build a three-dimensional ‘organ on a chip’, which enables real-time continuous monitoring of cells, and could be used to develop new treatments for disease while reducing the number of animals used in research. Eventually, the technique could also be used with stem cells taken from a patient, in order to develop personalised treatments in future.

̽��ֱ��research was supported in part by the European Research Council, the Wellcome Trust and the Royal Society.

Reference:
Ye Liu et al. ‘Bio-assembling Macro-Scale, Lumenized Airway Tubes of Defined Shape via Multi-Organoid Patterning and Fusion.’ Advanced Science (2021). DOI: 10.1002/advs.202003332

A team of engineers and scientists has developed a method of ‘up-sizing’ organoids: miniature collections of cells which mimic the behaviour of various organs and are promising tools for the study of human biology and disease.

We need to find the right conditions to help the cells in mini-organs self-organise

Yan Yan Shery Huang

Catherine Dabrowska

3D projection of a multi-organoid aggregate

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Building ‘nanomachines’ in biological outer space

sj387 — Thu, 14 Nov 2013 12:21:24 +0000

Cambridge scientists have uncovered the mechanism by which bacteria build their surface propellers (flagella) – the long extensions that allow them to swim towards food and away from danger. ̽��ֱ��results, published this week in the journal Nature, demonstrate how the mechanism is powered by the subunits themselves as they link in a chain that is pulled to the flagellum tip.

Previously, scientists thought that the building blocks for flagella were either pushed or diffused from the flagellum base through a central channel in the structure to assemble at the flagellum tip, which is located far outside the cell. However, these theories are incompatible with recent research showing that flagella grow at a constant rate. ̽��ֱ��completely new and unexpected chain mechanism, in which subunits linked in a chain ‘pull themselves’ through the flagellum, transforms understanding of how flagellum assembly is energised.

̽��ֱ��research was led by Dr Gillian Fraser and Professor Colin Hughes in the ̽��ֱ��’s Department of Pathology and was funded by the Wellcome Trust.

Dr Lewis Evans, who carried out the research, remarked: “It’s exciting how economical bacteria are, able to harness the thermal free energy from unfolded subunits and convert it into a coherent directed transport. More broadly, it’s fascinating to imagine the implications for how heat energy (normally considered as ‘lost’) might be harnessed to drive processes even outside living cells.”

As each flagellum ‘nanomachine’ is assembled, thousands of subunit ‘building blocks’ are made in the cell and are then unfolded and exported across the cell membrane. Like other processes inside cells, this initial export phase consumes chemical energy. However, when subunits pass out of the cell into the narrow channel at the center of the growing flagellum, there is no conventional energy source and they must somehow find the energy to reach the tip.

̽��ֱ��team has shown that at the base of the flagellum, subunits connect by head-to-tail linkage into a long chain. Together with Professor Eugene Terentjev, at the Cavendish Laboratory, they showed that the chain is pulled through the entire length of the flagellum channel by the entropic force of the unfolded subunits themselves. This produces tension in the subunit chain, which increases as each subunit refolds and incorporates into the tip of the growing structure. This pulling force automatically adjusts with increasing flagellum length, providing a constant rate of subunit delivery to the assembly site at the tip.

Professor Terentjev noted that this breakthrough can be applied to other fields. “Understanding how polymers move through channels is a fundamental physical problem. Gaining insight into this has potential applications in other disciplines, for instance in nanotechnology, specifically the building of new nanomaterials.”

This research has far-reaching implications, according to Fraser. “By understanding the base-level, fundamental biology of medically important bacteria and their construction of flagella and related toxin-injecting molecular syringes,” she commented, “we can start to develop new ways to counteract them.”

Dr Gillian Fraser is at Queens' College; Professor Colin Hughes is at Trinity College; Professor Eugene Terentjev is at Queens' College

New research reveals how bacteria construct tiny flagella ‘nanomachines’ outside the cell.

It’s exciting how economical bacteria are, able to harness the thermal free energy from unfolded subunits and convert it into a coherent directed transport

Dr Lewis Evans

Lewis Evans

Flagellated cell

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