A new study from the Salk Institute has revealed that a protein called BCL6 is key to maintaining healthy muscle mass. The experiments showed that mice with lower levels of BCL6 had significantly reduced muscle mass and strength, but increasing BCL6 successfully reversed those losses. The results suggest that pairing GLP-1 medications with a BCL6-boosting drug may help counteract unwanted muscle loss. Similar therapies could also be used to treat other populations prone to muscle loss, such as older adults and patients with systemic diseases like sepsis or cancer.

The findings were published in Proceedings of the National Academy of Sciences on January 22, 2025.

“Muscle is the most abundant tissue in the human body, so its maintenance is critical to our health and quality of life,” says Ronald Evans, professor and director of the Gene Expression Laboratory at Salk. “Our study reveals how our bodies coordinate the upkeep of all this muscle with our nutrition and energy levels, and with this new insight, we can develop therapeutic interventions for patients losing muscle as a side effect of weight loss, age, or illness.”

Going too long without eating puts your body in a fasted state. When this happens, your empty stomach sends a hormone called ghrelin to your brain to say, “I’m hungry!”The brain responds by releasing growth hormone into the rest of your body, where it regulates growth and metabolism in your many cells, tissues, and organs. As it travels through your body, growth hormone latches on to cells and directs them to make another protein called insulin-like growth factor 1 (IGF1), which then does the important work of controlling muscle growth.

In the time between growth hormone’s arrival and IGF1 synthesis, there is a complex web of proteins that determine how much IGF1 is made. One such protein is SOCS2, which slows down IGF1 production. Without SOCS2, IFG1 production runs out of control and causes gigantism. On the other hand, too much SOCS2 means not enough IFG1, leading to losses in body size and strength.

Still, SOCS2 is only one player in the path between growth hormone and IGF1. To protect people from rapid muscle loss, Salk scientists needed to get a clearer picture of the mechanisms underlying muscle maintenance. In search of other potential players, the researchers scoured a national database of human tissue samples and noticed an abundance of BCL6 in muscle cells — a clue that it may play an important role in this process.

To determine whether BCL6 was involved in muscle maintenance, the team compared mice with and without functional BCL6 proteins. Mice lacking BCL6 had 40% less muscle mass than their healthy counterparts, and the muscle they did have was compromised both in structure and function. However, when the researchers increased the expression of BCL6 in the animals’ muscles, this successfully reversed the losses in muscle mass and strength. And when they compared normal mice and those that had fasted overnight, they found fasting mice had less BCL6 in their muscles.

Clearly, BCL6 was controlling muscle maintenance — but how?

Through a series of subsequent experiments, the steps along the path became clear. Fasting promotes the secretion of growth hormone, which reduces BCL6 levels in muscle cells. BCL6 is a regulator of SOCS2, so less BCL6 leads to less SOCS2. At normal levels, this allows BCL6 to control how much SOCS2 is expressed and therefore how much IGF1 is made. In animals without BCL6, the lack of control over SOCS2 slowed IGF1 production so much that muscles became weaker and smaller.

“We are excited to reveal BCL6’s important role in maintaining muscle mass,” says first author of the study Hunter Wang, a postdoctoral researcher in Evans’ lab. “These were very surprising and special findings that open the door for a lot of new discoveries and potential therapeutic innovations.”

For GLP-1 patients hoping to lose weight while retaining muscle mass, it’s possible that a BCL6-boosting injectable could hit the market one day. In the meantime, the researchers plan to investigate what effects longer-term fasting has on BCL6 and muscle maintenance. Wang also notes that hormones tend to operate in cycles and that BCL6 naturally rises and falls with a strong circadian rhythm. A better understanding of this pattern may help further elucidate BCL6’s relationship with growth hormone and muscle growth.

Other authors include Hui Wang, Weiwei Fan, Sihao Liu, Kyeongkyu Kim, Satoshi Ogawa, Hyun Gyu Kang, Jonathan Zhu, Gabreila Estepa, Mingxiao He, Lillian Crossley, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk; Ayami Matsushima of Kyushu University; Christopher Liddle of University of Sydney; and Minseok Kim of Daegu Gyeongbuk Institute of Science and Technology.

The work was supported by the National Institutes of Health (P01 HL147835, DK057978, DK120515, CCSG P30 CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), Department of the Navy Office of Naval Research (N00014-16-1-3159), Larry Hillblom Foundation (2021-D-001-NET), Wu Tsai Human Performance Alliance, American Heart Association (916787), Salk GT3 (RRID:SCR_014847) and Waitt Advanced Biophotonics (RRID:SCR_014838) Core Facilities, San Diego Nathan Shock Center, Henry L. Guenther Foundation, and Waitt Foundation.

“This is a surface where pathogens can sneak in,” says La Jolla Institute for Immunology (LJI) Assistant Professor Miguel Reina-Campos, Ph.D. “That’s a massive challenge for the immune system.”

So how do immune cells keep the gut safe? New research led by scientists at LJI, UC San Diego, and the Allen Institute for Immunology shows that pathogen-fighting immune cells called tissue-resident memory CD8 T cells (T_RM cells) go through a surprising transformation — and relocation — as they fight infections in the small intestine.

In fact, these cells literally rise up higher in the tissue to fight infections before pathogens can spread to deeper, more vulnerable areas.

“The tissue in the gut has evolved to provide signals to immune cell infiltrates — to put immune cells in specific places so they have a better ability to stop pathogens,” says Reina-Campos, who served as first author of the new Nature study alongside co-first author Alexander Monell of UC San Diego and co-senior authors Maximilian Heeg, M.D., and Ananda W. Goldrath, Ph.D., of the Allen Institute for Immunology and UC San Diego.

The new findings add to the growing body of evidence that immune cells adapt to protect specific tissues. Reina-Campos thinks these “tissue-resident” immune cells may be key players in future cancer immunotherapies that target tumors in specific organs.

T cells on the move

Reina-Campos and his colleagues investigated the formation of T_RM cells in the small intestine. The team harnessed a cutting-edge technology called spatial transcriptomics to track these cells in both human and mouse tissue samples.

Their work showed that the small intestine holds two types of T_RM cells. These cells are split between the tiny, finger-like “villi” structures that line the small intestine or the “crypts” between the protruding villi.

The researchers found that progenitor-like T_RM cells live closer to the crypts between the villi. On the other hand, differentiated T_RM occupy more exposed regions at the top of the villi. “Differentiated immune cells are more exposed at the top of the villi, and that’s where they have a better ability to protect you from infections,” says Reina-Campos.

Meanwhile, a reserve population of progenitor-like T_RM cells continues to lie low in the crypts. “These cells can replenish the pool of effector T cells, so the immune system keeps them as back-ups in the deeper parts of the tissue,” adds Reina-Campos.

What keeps these populations organized and in check?

To spy on these important immune cells within their natural habitat, Reina-Campos and colleagues used a new technology — called spatial transcriptomics — to observe millions of messenger RNA molecules simultaneously at subcellular resolution.

“For the first time, we were able to capture the formation of immunological memory in space and time,” says Reina-Campos.

Looking at small intestines after a viral infection, the scientists found that the gut releases chemical signals to instruct immune cells where to go and what to do. “This study offers a new resource for finding signals that position immune residents to strengthen our gut immunity,” says Reina-Campos.

Checkmate for disease?

Reina-Campos credits his mentor, Goldrath, as well as Heeg’s and Monell’s expertise for making this study possible. As Reina-Campos explains, Heeg and Monell developed new computational approaches to make sense of the massive amounts of data captured through spatial transcriptomics.

“It’s led to a breakthrough in our ability to look at hundreds to thousands of genes simultaneously in intact tissues,” says Reina-Campos. “With this study, we’ve opened up a new path for discovery.”

Reina-Campos compares the battle between immune cells and pathogens to a chess match.

“To be a chess grandmaster, you need to know not only about the pieces: the bishops, pawns, rooks, etc, but also how they move in concert on the chessboard,” he says.

For a long time, scientists have studied the chess pieces — by analyzing cells extracted from tissue — but they haven’t gotten a good look at the chess match itself. “We don’t know as much about how the chessboard works — and we know even less about the rules that apply to our chess pieces as they move across the board,” says Reina-Campos.

The new study gives researchers a detailed look at how immune cells interact with each other and their cellular gameboard.

Reina-Campos says the new finding should guide future research into how immune cells develop and move through other organs with different tissue structures, such as the kidneys and lungs — and how immune cells might fight tumors in these organs.

Influence of very early life stages

The research team investigated how maternal stress affects the stress hormone system of the offspring. They found that the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which plays a central role in coping with stress, can be significantly influenced by exposure to maternal glucocorticoids during development. The early phase of organ differentiation in the first half of pregnancy proved to be a particularly critical period. “Our results show that the HPA-axis activity of offspring was enhanced, the more adversity the other had experienced during early pregnancy — which could be food shortages or social conflicts for example,” says Simone Anzá, former doctoral student at the University of Göttingen and the German Primate Center and first author of the study.

Investigation in the wild

In contrast to studies in the laboratory, the monkeys were observed in their natural habitat. Over a period of nine years, the researchers repeatedly collected fecal samples from pregnant females and measured the concentration of glucocorticoid metabolites in them in order to determine the animals’ exposure to environmental factors such as food scarcity, temperature fluctuations and social interactions. These values were compared with the stress hormone levels of the offspring at different ages. The effects on the stress axis of the offspring were evident from infancy through the juvenile period and into adulthood at nine to ten years of age. Previous analyses from the same study had already shown that early prenatal stress was also associated with altered growth, negative changes in the gut microbiome and impaired immune function, underlining the comprehensive influence of the environment in the early prenatal period on various physiological systems. In contrast, maternal glucocorticoid levels in late pregnancy or during lactation had no or different influences.

Relevance for health research

“Our research results indicate that the timing of maternal stress hormone exposure during and after pregnancy crucially affects the consequences for the development and health of the offspring. It is also important to note that these effects do not require catastrophic events, but that even moderate changes in environmental conditions are sufficient,” says Oliver Schülke, scientist at the University of Göttingen and the German Primate Center and head of the study. Stress in early pregnancy can also have a long-term effect on health in humans and increase the risk of stress disorders and immune problems. “Our findings may help to identify the timing and mechanisms that preventive measures should address in order to reduce long-term health risks,” says Oliver Schülke.

The Geiseltal Saxony-Anhalt is located south-west of Halle and was a lignite mining area until 1993. Numerous exceptionally well-preserved animal fossils have been unearthed here. The Geiseltal Collection at MLU comprises 50,000 fossils and is considered a national heritage asset. These fossils offer unique insights into the evolution of animals and the Eocene Epoch around 45 million years ago. At that time, the Geiseltal was a warm, tropical swamp. Ancient horses, early tapirs, large land crocodiles as well as giant tortoises, lizards and numerous birds lived here. Some of the latter were flightless and the largest of these was Diatryma, a herbivore with a gigantic beak which stood around 4.6 feet high.

For many years no one knew that an almost completely preserved skull of Diatryma was part of the collection. “The find was initially misidentified as a crocodile skull,” says Michael Stache, a geological preparator at MLU’s Central Repository of Natural Science Collections. Stache came across the fossil again by chance several years ago. He realised the mistake and got down to work, restoring and then analysing the piece of skull. He combined the fossil with another object from the collection, reconstructing an almost entire skull. Dr Gerald Mayr, a researcher at the Senckenberg Institute, examined the find more closely and realised its importance: the skull clearly belonged to a Diatryma. Only one other fully preserved skull is known to exist in the world and is housed in the American Museum of Natural History in the USA.

“This shows once again that many of the most interesting discoveries in palaeontology occur in museum collections. Just a few years ago, nobody would have thought that the Geiseltal Collection would contain such surprises,” says Gerald Mayr. Michael Stache also reports that there is great scientific interest in the fossils. Researchers from Germany and abroad come to MLU on a regular basis to investigate the objects. “This research expands our understanding of the Eocene Epoch in the Geiseltal even though the excavations were completed long ago,” says Michael Stache. Up until ten years ago, for example, it was assumed that Diatryma hunted prehistoric horses in the Geiseltal. More recent investigations have found that the bird was, in fact, a herbivore.

There are around 40 specimens of the bird in the Geiseltal Collection. “Diatryma was probably a rare guest in the Geisetal. Otherwise, there would probably be more fossils,” concludes Stache.

These nano-sized motors are highly programmable and can be designed for use in molecular computation, diagnostics, and transport. Despite their genius, DNA-nanoparticle motors don’t have the speed of their biological counterparts, the motor protein, which is where the issue lies. This is where researchers come in to analyze, optimize, and rebuild a faster artificial motor using single-particle tracking experiment and geometry-based kinetic simulation.

“Natural motor proteins play essential roles in biological processes, with a speed of 10-1000 nm/s. Until now, artificial molecular motors have struggled to approach these speeds, with most conventional designs achieving less than 1 nm/s,” said Takanori Harashima, researcher and first author of the study.

Researchers published their work in Nature Communications on January 16th, 2025, featuring a proposed solution to the most pressing issue of speed: switching the bottleneck.

The experiment and simulation revealed that binding of RNase H is the bottleneck in which the entire process is slowed. RNase H is an enzyme involved in genome maintenance, and breaks down RNA in RNA/DNA hybrids in the motor. The slower RNase H binding occurs, the longer the pauses in motion, which is what leads to a slower overall processing time. By increasing the concentration of RNase H, the speed was markedly improved, showing a decrease in pause lengths from 70 seconds to around 0.2 seconds.

However, increasing motor speed came at the cost of processivity (the number of steps before detachment) and run-length (the distance the motor travels before detachment). Researchers found that this trade-off between speed and processivity/run-length could be improved by a larger DNA/RNA hybridization rate, bringing the simulated performance closer to that of a motor protein.

The engineered motor, with redesigned DNA/RNA sequences and a 3.8-fold increase in hybridization rate, achieved a speed of 30 nm/s, 200 processivity, and a 3 μm run-length. These results demonstrate that the DNA-nanoparticle motor is now comparable to a motor protein in performance.

“Ultimately, we aim to develop artificial molecular motors that surpass natural motor proteins in performance,” said Harashima. These artificial motors can be very useful in molecular computations based on the motion of the motor, not to mention their merit in the diagnosis of infections or disease-related molecules with a high sensitivity.

The experiment and simulation done in this study provide an encouraging outlook for the future of DNA-nanoparticle and related artificial motors and their ability to measure up to motor proteins as well as their applications in nanotechnology.

Takanori Harashima, Akihiro Otomo, and Ryota Iino of the Institute for Molecular Science at National Institutes of Natural Sciences and the Graduate Institute for Advanced Studies at SOKENDAI contributed to this research.

This work was supported by JSPS KAKENHI, Grants-in-Aid for Transformative Research Areas (A) (Publicly Offered Research) “Materials Science of Meso-Hierarchy” (24H01732) and “Molecular Cybernetics” (23H04434), Grant-in-Aid for Scientific Research on Innovative Areas “Molecular Engine” (18H05424), Grant-in-Aid for Early-Career Scientists (23K13645), JST ACT-X “Life and Information” (MJAX24LE), and Tsugawa foundation Research Grant for FY2023.

Scientists have discovered that juvenile bottlenose dolphins have specialized receptors for detecting the fatty acids in their mother’s milk. These findings, published in the journal Marine Mammal Science, offer important insights into how these marine mammals grow, feed, and communicate.

The new findings challenge previous assumptions about cetacean sensory systems. Unlike land mammals, dolphins and other marine mammals have limited olfactory capabilities – their sense of smell is largely nonfunctional in aquatic environments. Researchers have therefore speculated that dolphins had other ways of sensing their surroundings and detecting food.

Fat plays an essential role in providing energy and supporting brain development in dolphin calves, which are entirely dependent on their mother’s milk during their early stages of life.

“We looked at the tongue of a young Indo-Pacific bottlenose dolphin and confirmed special structures that may help it detect fat,” says the study’s first author Hinako Katsushima of the Graduate School of Environmental Science at Japan’s Hokkaido University. “At the back of the tongue, there’s a V-shaped row of taste receptors that are specifically tuned to pick up fatty acids. These receptors also have enzymes that help break down the fat, making it easier for the dolphin to sense and process it.”

In a second experiment, the team gave young dolphins a choice between two liquids: one containing milk and the other a cloudy solution. The dolphin showed an unexpected preference for the cloudy solution. This reinforces the finding that dolphins can distinguish between the two liquids, but the researchers are unsure why they avoided the milk. One possibility is that they found the milk unfamiliar – it was a mixture of milk from two females – and so avoided it from a fear of new foods, a habit called neophobia.

“Our findings suggest that the ability to detect fatty acids in their mother’s milk is part of a specialized ‘fat taste’ system that could help dolphins assess the nutritional value of their food,” says Assistant Professor Takashi Hayakawa from the Faculty of Environmental Earth Science at Hokkaido University, who led the study. “In the wild, where fat-rich diets are critical for survival, this capability may provide dolphins with an evolutionary advantage, allowing them to select high-quality milk from their mothers and later evaluate the nutritional content of their prey.”

The new study opens new avenues for understanding how marine mammals perceive and interact with their environment, as well as how they communicate and forage in the wild. Further research will be necessary to explore the full scope of this “fat taste” system and how it functions in other marine species.