Ryosuke Okino / Muscle Biology, Research Team for Aging Science
・Introduction
Skeletal muscle is not only the primary locomotor system for daily activities but also the organ with the highest energy metabolism in the body. A decline in the quality and quantity of skeletal muscle increases the risk of aging-related metabolic disorders, such as sarcopenia and type 2 diabetes, which are prevalent in our society. Consequently, maintaining skeletal muscle mass throughout life is directly associated with increased healthy life expectancy and is essential for living fulfilling lives into one's 100s.
Skeletal muscle exhibits rapid regeneration following injury, such as that caused by strenuous exercise. These muscles adapt in mass according to activity levels, demonstrating plasticity. Subjecting them to stress through strength training results in hypertrophy, while inactivity--due to lack of exercise or prolonged hospitalization--leads to atrophy (Figure 1). Our research group aims to develop a technology for controlling muscle aging to extend healthy life by elucidating the mechanisms of skeletal muscle regeneration and plasticity, as well as understanding how these mechanisms change with aging and disease.
Figure 1. Plasticity of skeletal muscle
・ Skeletal muscle growth and atrophy
Skeletal muscle comprises bundles of multinucleated muscle fibers, which are encased by tissue stem cells known as satellite cells. When activated by muscle damage or growth factors, satellite cells differentiate into myoblasts. These myoblasts either fuse with one another to create new muscle fibers or integrate with existing fibers (Figure 2). Muscle fibers primarily consist of contractile proteins such as myosin and actin, and muscle mass is influenced by the balance between their synthesis and degradation. Resistance training induces muscle hypertrophy by promoting muscle protein synthesis beyond the rate of degradation, while inactivity leads to atrophy due to increased degradation. The decline in muscle mass and function associated with aging or clinical conditions is attributed to factors such as muscle protein degradation outpacing synthesis, a reduction in the number of muscle fibers, a decrease in both the number and functionality of satellite cells, and the regression of motor neurons that govern muscle contraction.
Figure 2. Skeletal muscle regeneration/growth patterns
・Region-Specific Mechanisms of Muscle Mass Control
The size and shape of skeletal muscles vary by anatomical location, and their functions extend beyond movement to include postural maintenance, breathing, chewing, swallowing, and facial expressions. Recent studies have revealed that the properties of skeletal muscle are not uniform throughout the body. While skeletal muscles are characterized by their regenerative capacity and plasticity, these attributes differ based on their location. For instance, leg muscles exhibit greater regenerative strength and grow faster in vivo compared to muscles in other regions; however, as individuals age, leg muscles tend to atrophy more rapidly than arm muscles. A similar pattern is observed in rats, where the hind limb are more prone to atrophy than the fore limb. Conversely, although the regenerative capacity of head muscles is limited, they show resistance to age-related and disease-related atrophy (references 1, 2). These region-specific differences cannot be solely attributed to variations in muscle fiber types or levels of physical activity, suggesting the existence of region-specific control mechanisms. Research on region-specific differences in skeletal muscles is limited, with most findings derived from basic studies focusing predominantly on leg muscles. Therefore, gaining insights into these mechanisms holds promise for developing preventive therapies for various muscle conditions, including sarcopenia.
・Toward an insight into Region-Specific Mechanisms of Muscle Mass Control
To gain insight into region-specific mechanisms of muscle mass control , we have concentrated on Hox genes, which are critical for positional determination during fetal development. Hox genes orchestrate the construction of the body and the patterning of extremities along the anterior-posterior axis during fetal development. Mammals possess four clusters of Hox genes, designated Hox-A through Hox-D, with each cluster comprising 13 types. During fetal development, specific Hox genes are expressed in appropriate combinations and timing for each body region to ensure accurate body formation (Figure 3). While the functionality of these Hox genes has primarily been investigated during fetal development, recent studies suggest they also have roles in adults.
Figure 3. Body region-specific Hox gene expression
We first analyzed skeletal muscles at various sites in adults, focusing on the expression patterns of satellite cell Hox genes. Our findings revealed no Hox gene expression in head muscles, while high expression levels of Hox-A and Hox-C cluster genes were observed in limb muscles. Investigations of muscle function in mice lacking satellite cell specificity indicated that the HoxA10 gene did not influence satellite cells in resting muscles; however, muscle regeneration was significantly impaired following damage to the anterior tibial muscle. Additionally, no regeneration failure was observed in head muscles, where HoxA10 is not expressed, indicating that HoxA10 expression is site-dependent and primarily governs the regeneration of limb muscles (reference 3). Based on these results, we propose that satellite cells in different body sites exhibit gene expression patterns characteristic of specific genes, including Hox genes (positional memory), which may regulate skeletal muscle function in a site-specific manner (references 4, 5). As the distribution of Hox gene expression in skeletal muscles is preserved across species, including humans, we aim to continue our research to clarify the relationship between positional memory and muscle disease.
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