"Maintaining muscle mass is the best way to combat aging, as muscles are not just for movement but also play a crucial role in regulating the body's metabolism. I recommend older adults and working individuals to engage in moderate to high-intensity and endurance exercises within their capabilities."
As people age, they often notice a decline in muscle function compared to their younger years. Many older adults experience sudden falls, leading to severe consequences and even life-threatening situations. Some older adults, however, maintain excellent physical performance, with some even outperforming younger individuals. A recent study has unveiled the mysteries of muscle aging by analyzing various changes in muscle cells.
Researchers use multiple indicators to evaluate muscle function, forming the most comprehensive skeletal muscle multi-modal single-cell atlas to date. Image Source: "Nature"
This study was published on April 22, 2024, in the journal "Nature" by researchers from various institutions both domestic and international, including Hangzhou Hua Da Institute of Life Sciences in China, Pompeu Fabra University in Spain, the First Affiliated Hospital of Guangdong Pharmaceutical University, Altos Labs, Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences, and the Fifth Affiliated Hospital of Guangzhou Medical University.
Researchers obtained muscle biopsy samples from the lower limbs of 31 participants from Spain and China (17 males and 14 females) and categorized them into adult group (ages 15 to 46) and elderly group (ages 74 to 99) for comparison. They used various indicators to assess muscle function and conducted single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), and single-nucleus ATAC sequencing (snATAC-seq). The study analyzed and integrated this information to create the most comprehensive skeletal muscle multi-modal single-cell atlas to date.
The study identified various cellular changes and regulatory mechanisms during muscle aging. For example, with increasing age, explosive fast muscle fibers gradually decrease while more endurance-oriented slow muscle fibers remain relatively stable. Although the number of muscle stem cells responsible for repair and proliferation decreases significantly in older individuals, new muscle fibers with unique protective functions also emerge.
How was this cellular atlas created? What cells make up our muscles? What are the characteristics of muscle aging? How can older individuals maintain muscle health and improve physical performance? To answer these questions, Pengpai Technology recently interviewed the first author of this study, Vice Researcher Lai Yiwei from Hangzhou Hua Da Institute of Life Sciences.
[Dialogue]
International Collaboration Creates Muscle Cell Atlas
Pengpai Technology: This study utilized single-cell and single-nucleus sequencing technologies to create a multi-modal cell atlas of human skeletal muscle. Could you briefly explain how this sequencing is conducted? How were the samples collected and analyzed? How long did it take to create the atlas? In what aspects does the "multi-modal" feature primarily manifest?
Lai Yiwei (Vice Researcher at Hangzhou Hua Da Institute of Life Sciences): Single-cell sequencing is a technology used to study gene expression and genomic information of individual cells. In this study, we utilized Hua Da's independently developed single-cell library construction and sequencing platform. Individual cells and nuclei isolated from tissues were added to a droplet generation device, encapsulating each cell (nucleus) in a droplet structure where the information of each cell (nucleus) could be captured and detected through sequencing methods.
It took us three to four years to complete the creation of the human skeletal muscle multi-modal cell atlas in this study. The term "multi-modal" mainly refers to obtaining information on both the transcriptome and regulatory elements on the genome.
Pengpai Technology: This study was a collaborative effort among various international institutions. Could you introduce the background and process of this collaboration? Where did the research funding primarily come from?
Lai Yiwei: In 2019, Hua Da independently developed a single-cell sequencing technology, DNBelab C4. At that time, my mentor, Researcher Miguel A. Esteban, and Researcher Liu Longqi from Hua Da invited numerous scholars from both domestic and international institutions to discuss the application of this technology, including the internationally renowned muscle research expert, Researcher Pura Mu?oz-Cánoves from Pompeu Fabra University in Spain. It was believed that single-cell genomics research should be expanded to the entire field of aging and regeneration, with muscle aging being a significant component. Eventually, we formed a research team, including Director Song Yancheng from the Orthopedics Department of the First Affiliated Hospital of Guangdong Pharmaceutical University, as well as teams from Valencia University and hospitals domestically and internationally, to jointly complete this study.
The research funding for this project came from self-raised funds of Hua Da Institute of Life Sciences, as well as from the National Natural Science Foundation, the National Key Research and Development Program, and other sources. The research conducted by international collaborators received support from universities and local governments.
Muscle Aging: Decline in Explosive Power, Harder to Repair
Pengpai Technology: The study revealed observations on various muscle cell types, including muscle fibers, muscle nuclei, muscle stem cells, fibro-adipogenic progenitor cells, etc. Could you introduce these cell types and their functions?
Lai Yiwei: Muscle fibers are the basic units of muscle tissue and are commonly referred to as muscle fibers. They are composed of many myofibrils. Muscle fibers are the primary contractile units of muscles.
Muscle nuclei refer to the cell nuclei within muscle fibers. During muscle development, muscle nuclei fuse to form multi-nucleated muscle fibers. Muscle nuclei are mainly responsible for synthesizing and maintaining the proteins and other cellular components required by muscle fibers.
Muscle stem cells are a type of multipotent stem cells, also known as satellite cells. They are located beneath the basal lamina surrounding muscle fibers and are in a dormant state. When muscle tissue is damaged or stimulated, muscle stem cells activate and differentiate into new muscle fibers to repair and grow muscle tissue.
Fibro-adipogenic progenitor cells are a type of multi-potent cells found in muscle tissue. They have the potential to differentiate into fibroblasts or adipocytes. Fibro-adipogenic progenitor cells play a crucial regulatory role in muscle repair and regeneration processes, participating in the formation of muscle fiber structures and regulating fibrosis and fat deposition in muscle tissue. In addition, there are vascular endothelial cells, immune cells, and so on. These cells play important roles in muscle function, repair, and regeneration.
Pengpai Technology: A study compared the differences in muscle cells between young and elderly individuals. Could you please introduce the main findings?
Lai Yiwei: The study found that with age, fast muscle fibers gradually decrease, while slow muscle fibers remain relatively stable. Researchers identified molecular pathways of fast and slow muscle fiber degeneration, revealing differences in the mechanisms of muscle fiber degeneration. Slow muscle fibers showed better tolerance to aging stress.
Furthermore, as people age, new groups of muscle fibers appear in the muscles. These muscle fibers are rarely seen in young individuals but increase in number in the elderly, such as repair-type and degenerative-type muscle fiber subtypes. Degenerative types may be the first group to age in muscle fiber degeneration, while repair types play a special protective role in the elderly, helping maintain muscle function and slowing down the aging process.
We also found that during aging, muscle stem cells enter a state of continuous activation, leading to their depletion in aging; endothelial cells show increased pro-inflammatory and chemotactic signals, while the number of immune cells increases and initiates an inflammatory process. These changes suggest that aged muscles are less capable of repair when damaged and may promote systemic inflammation, accelerating the overall decline in elderly individuals' physical function.
Pengpai Technology: The study included participants from Spain and China. How does race affect the process of muscle aging?
Lai Yiwei: Currently, the aging processes and mechanisms on both sides are consistent. However, due to limitations in the number of individuals, we are unable to further analyze the differences between them.
Staying Active for Healthy Aging
Pengpai Technology: Could you briefly introduce muscle atrophy? In what situations is muscle degeneration considered a disease? How is it diagnosed?
Lai Yiwei: Muscle atrophy, also known as myasthenia or muscle wasting, is a group of diseases that affect muscle function and size. These diseases lead to muscle weakness, atrophy, and reduction, affecting the body's movement and daily activities.
Diagnosing muscle atrophy typically requires considering multiple aspects such as medical history, physical examination, nerve-muscle electromyography, and muscle biopsy evidence. Age-related muscle wasting is often not considered a disease due to its common occurrence, but it significantly impacts the mobility of elderly individuals. When muscle wasting reaches a certain level, elderly individuals may not be able to support their own weight, leading to frequent falls and injuries. These falls or accidents can have serious consequences on the health and life of elderly individuals, with the most severe injuries often referred to as the "last fall" of the elderly.
Pengpai Technology: Based on the research results, what interventions can help people maintain muscle health? What new insights does the research provide for the treatment of muscle atrophy?
Lai Yiwei: Balanced diet, adequate rest, maintaining a healthy weight range, avoiding smoking and excessive alcohol consumption, and regular exercise, including some high-intensity and endurance exercises, all contribute to maintaining muscle health.
This study provides a quantitative standard for diagnosing age-related muscle wasting at the cellular and molecular levels. Subsequent researchers can match the cellular or molecular characteristics in patient muscle samples to the muscle aging single-cell atlas published in this study to quantify the degree of muscle aging. Additionally, the cell subtypes identified in the aging process in this study may provide a scientific basis for targeted therapies for age-related muscle wasting in the future, potentially offering the possibility of reversing muscle aging, which could also have implications for treating amyotrophic lateral sclerosis.
Pengpai Technology: Since muscle decline is inevitable, should elderly individuals no longer have expectations of improving muscle performance? What advice do you have for elderly individuals who wish to maintain muscle strength and function?
Lai Yiwei: Not necessarily. Although muscle decline is inevitable, we have found significant heterogeneity among elderly individuals, with some having relatively better health conditions than others. In fact, maintaining muscle levels is the best way to combat aging because muscles are not just organs for movement but also crucial for maintaining overall metabolism. I recommend that elderly individuals and working professionals engage in some degree of high-intensity and endurance exercises within their capabilities.
