No Sugar, No Problem: Skeletal Muscle Cells Thrive in Low-Sugar Environments to Prevent Age-Related Muscle Loss

From microscopic bacteria swimming through tiny spaces to plants tilting and turning towards the sun to animals migrating across continents and oceans, the ability to move is a fundamental characteristic of all living organisms — no matter how brainless they might be. However, what bacteria and plants don’t have to support their movements is muscular tissue. One vital type of muscular tissue is skeletal muscle, giving humans the ability to move and perform various activities, ranging from the everyday minutiae of brushing your teeth or tying your shoes to major bursts of movement, like sprinting down a field or climbing up a hill. 

Unfortunately, we don’t have an unlimited supply of skeletal muscle. As early as age 30, our skeletal muscle mass and strength progressively decrease, with 80-year-olds commonly losing 50% or more of the muscles they had when they were young. Also known as sarcopenia, this drastic reduction in muscle amount and capacity in older adults leads to a decline in quality of life and independence with an increased risk of frailty, falls, fractures, and mortality. 

Although many factors are at play when it comes to sarcopenia, some researchers believe that chronically high blood sugar (hyperglycemia) is implicated in this age-related muscle loss. In a recent study, researchers out of Tokyo Metropolitan University in Japan add to the evidence that high blood sugar is indeed detrimental to muscle growth and repair. By manipulating the glucose (sugar) levels in petri dish cultures of specific muscle cells, Furuichi and colleagues find that lower glucose levels provide the optimal conditions for skeletal muscle cells to grow, going against the previously held belief that all proliferating cells thrive in sugar-rich environments.

In this study, the Tokyo-based team further elucidates how hyperglycemia impacts muscle repair, which could have wide-reaching effects for both treating sarcopenia and opening new doors for studying regenerative muscle growth in biomedical research.

Sugar and Sarcopenia: The Not-So-Sweet Stuff

One group of cells that are highly involved in muscle regeneration are satellite cells, which are stem cells that are specific to the skeletal muscle. When a muscle is damaged — whether from injury, disease, or age-related loss — satellite cells can proliferate, or multiply, into precursor cells called myoblasts, which have yet to fully form the shape and function of developed muscle cells. From there, the myoblasts differentiate, or change, into muscle cells called myocytes, which fuse to form muscle fibers and repair the damaged muscles. 

However, this process of muscle regeneration, which is essential for maintaining muscle mass with age, is impaired by hyperglycemia — one study found that having type 2 diabetes increased the risk of sarcopenia by threefold compared to those without diabetes. Research has found that this is a two-way relationship. In addition to diabetes leading to sarcopenia, muscle loss also increases the risk of diabetes. A third player in this scenario is obesity, as excess body weight and fat stores contribute to both diabetes and sarcopenia, while low motility due to sarcopenia can further increase obesity. As sarcopenia is both a cause and consequence of diabetes and obesity, mitigating this age-related muscle loss by lowering blood sugar could reduce the risk of these three diseases that are highly prevalent in older adults, improving both health- and lifespan.

Survival of the Satellite Cells

Contrary to the previous notion that most cells require high amounts of sugar to multiply, Furuichi and colleagues find that skeletal muscle satellite cells prefer — and thrive — under low-glucose conditions. After isolating and culturing satellite and other muscle cells from young mice, the research team looked at various markers of cell health and growth in low- or high-glucose environments. 

In the low-glucose group, which was about one-tenth as sugary as the high-glucose group, the satellite cells had significantly higher proliferation rates and lower rates of apoptosis — programmed cell death. This indicates that glucose restriction facilitates satellite cell growth and viability, while mitigating cell damage and death. In the high-glucose cultures, which were equivalent to the blood sugar levels of someone with uncontrolled diabetes, the cells’ proliferation stopped after one week, whereas the low-sugar group continued to multiply for over two weeks. The low-sugar cell group also had the capacity to differentiate into myocytes, which could go on to regenerate or repair muscle if these cell cultures were translated to humans.

Most cells prefer sugar-rich environments because glucose can be used to create ATP (energy), leading the researchers to wonder if there was a particular bottom-line of sugar concentration that these satellite cells preferred. To test this, Furuichi and colleagues added an enzyme called glucose oxidase, which essentially digests and depletes glucose. In this culture with no glucose at all, the satellite cells still thrived and multiplied. Myoblasts — the precursors to fully developed myocytes — also functioned well in the low-glucose culture. These precursor cells continued to multiply for over two weeks and expressed a protein that is indicative of normal differentiation into muscle cells. They also found that these results didn’t apply to all cells, as other non-muscle cells that commonly overgrow in satellite cell cultures were unable to proliferate in the low- and no-sugar conditions. These findings were unexpected, and although it’s clear that satellite cells get their energy from an entirely different fuel source than glucose, the researchers aren’t entirely sure yet what that source is — future research will tell. 

Making Moves in Muscle Regeneration Research

With these results come important implications for stem cell and regenerative medicine research. A leading problem in muscle regeneration research is that the satellite cell cultures get contaminated or overgrown with other non-muscle cells, as they thrive in higher-sugar scenarios and can overpower the low multiplication of satellite cells. As satellite cells are stem cells specific to skeletal muscle, having a pure and uncontaminated culture could provide many more opportunities for studying — and treating — muscle-related diseases, ranging from sarcopenia to muscular dystrophy. While we don’t know for sure if lowering blood sugar in humans would boost skeletal muscle growth and repair, these results are promising for their future potential in reducing the risk of sarcopenia, obesity, and type 2 diabetes. As summarized by the authors, “Our finding that glucose restriction increases the proliferation of cultured muscle cells revolutionizes the existing concepts.”

References:

Furuichi Y, Kawabata Y, Aoki M, Mita Y, Fujii NL, Manabe Y. Excess Glucose Impedes the Proliferation of Skeletal Muscle Satellite Cells Under Adherent Culture Conditions. Front Cell Dev Biol. 2021;9:640399. Published 2021 Mar 1. doi:10.3389/fcell.2021.640399

Kim TN, Park MS, Yang SJ, et al. Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS) [published correction appears in Diabetes Care. 2010 Oct;33(10):2294]. Diabetes Care. 2010;33(7):1497-1499. doi:10.2337/dc09-2310

Umegaki H. Sarcopenia and diabetes: Hyperglycemia is a risk factor for age-associated muscle mass and functional reduction. J Diabetes Investig. 2015;6(6):623-624. doi:10.1111/jdi.12365