Sarcopenia -- As Harmful As Osteopor osis But Less Well Known -- Is Better Explained By New Research

A mechanism is newly revealed which may explain why IL-6 is a strong risk factor for disability in muscle function

(April 1, 2003) Bethesda, MD -- The dangers associated with osteoporosis are justifiably conveyed in the electronic and print media, since this condition leading to a decrease in bone mass is responsible for 50 percent of the fractures incurred by women over age 50.  But an equally harmful condition, sarcopenia, surprisingly remains unknown to the millions that will suffer the results of this geriatric disorder.

Background

Sarcopenia is the condition when the lean muscle, which is one of the most metabolically active tissues (user of calories) in the human body, accelerates its erosion after age 45.  Lean muscle erosion is the single most important factor in the gradual accumulation of excess body fat. From events as subtle as buying your car to the consumption of an inadequate meal, your body through the compounding effects of an inadequate diet and a lack of regular exercise gradually begins to weaken.

Previous research has offered evidence suggesting that chronic inflammation is one of the most important biological mechanisms underlying the decline in physical function that is often observed over the aging process.  The plasma concentration of interleukin-6 (IL-6), a cytokine that plays a central role in inflammation, tends to increase with age. High serum levels of IL-6 are a predictive factor of disability in the elderly, and preliminary data contend that IL-6 is associated with accelerated sarcopenia.  However, the mechanism by which chronic inflammation affects physical function has not been fully established.

Several studies suggest that insulin-like growth factor I (IGF-I) is an important modulator of muscle mass and function not only during an individual’s developmental period but also across the entire life span. Recent findings of an epidemiological study performed in a large representative sample of older women show that low plasma IGF-I levels are associated with poor knee extensor muscle strength, slow walking speed, and self-reported difficulty with mobility tasks, thus suggesting a role of IGF-I in the causal pathway leading to disability in the elderly.  Additional research conducted demonstrated that IL-6 inhibits the secretion of IGF-I and its biological activity and that IL-6 overproduction is a mechanism implicated in IGF-I and insulin-like growth factor-binding protein (IGFBP)-3 downregulation. Furthermore, in transgenic mice, an IGF-I deficiency caused by IL-6-related mechanisms determined growth impairment.

A New Study

In light of such evidence, a potential effect of IL-6 and IGF-I in the regulation of the homeostatic mechanisms that maintain an adequate muscle mass can be claimed.  One hypothesis is that IL-6-affected IGF-I production may be a potential mechanism by which chronic inflammation causes impaired physical function.

Italian researchers joined a physiologist from the National Institute of Aging in evaluating the relationship of plasma concentrations of IGF-I and IL-6 with muscle function in a population-based sample of older persons.  The authors of “Chronic Inflammation and the Effect of IGF-I on Muscle Strength and Power in Older Persons” are Michelangela Barbieri, Emilia Ragno, and Giuseppe Paolisso, from the Department of Geriatric Medicine and Metabolic Diseases, II University of Naples, Naples; Luigi Ferrucci, Annamaria Corsi, and Stefania Bandinelli, at the Laboratory of Clinical Epidemiology, Italian National Research Council of Aging, Geriatric Department, Florence; Massimiliano Bonafe and Claudio Franceschi, from the Department of Experimental Pathology, University of Bologna, Bologna; Fabiola Olivieri and Simona Giovagnetti, from Italian National Research Centers on Aging, Ancona, all in Italy; and Jack M. Guralnik, at the Epidemiology, Demography, and Biometry Laboratory, National Institute of Aging, Bethesda, MD.  Their findings appear in the March 2003 edition American Journal of Physiology—Endocrinology and Metabolism, one of 14 journals published each month by the American Physiological Society (APS).

Methodology

The study population consisted of 526 subjects (mean age: male 65 + 15; female 66 +16).  Subjects affected by diabetes mellitus and major clinical cardiovascular diseases were excluded, as well as those taking drugs known to interfere with IGF-I and IL-6 metabolism. Clinical information was obtained by routine laboratory analyses and physical examination.

Blood samples were collected in the morning after the participants had been fasting for at least eight hours. Glucose level was immediately quantified by an enzymatic colorimetric assay using a modified glucose oxidase-peroxidase method and an analyzer.  Several 0.5-ml aliquots of serum were processed immediately and stored at 80°C and subsequently used for the assessment of hormones and cytokines. Plasma insulin and free IGF-I concentrations were determined. 

Isometric grip muscle strength was assessed using a hand-held dynamometer following a standardized measurement protocol that has been shown to provide highly reliable data.  Each muscle group was tested two times, and separate measures were obtained for the left and the right side for each hand. The best measure for the strongest side was used in the analysis.  Explosive muscle power of lower extremity in extension (physical work delivered to the external environment in a unit of time) was evaluated.

To approximate normal distributions, log-transformed values for plasma IL-6, triglycerides, insulin, and insulin resistance (HOMA) were used in the analyses.  Differences in continuous variable between males and females were tested with the Student’s t-test. Pearson product-moment correlations were calculated to test associations among variables.

Results

Study participants were slightly overweight with a mainly central body fat distribution.  Women had lower plasma IL-6 levels and lower handgrip strength and total power than men. In contrast, no gender difference in plasma IGF-I levels was found.  In the whole group, age was negatively correlated with handgrip and total power. Plasma IL-6 levels were positively correlated with age and body mass index and negatively correlated with total power and handgrip. Conversely, IGF-I was negatively correlated with age and BMI and positively correlated with total power and handgrip. Both IL-6 and IL-6 receptor serum concentrations were negatively correlated with IGF-I serum concentrations. As expected, IL-6 and IL-6 receptor were positively correlated

No differences in IL-6 plasma levels according to IL-6 promoter polymorphism were found..  Indeed, when stratifying subjects according to levels of plasma IL-6 levels, IL-6 promoter polymorphism was a significant predictor of IL-6 plasma levels (independently of age, sex, and BMI) in subjects at the highest level. In particular, lower plasma IL-6 levels were found in subjects carrying the allele C compared with no carrier subjects. To better investigate how IGF-I and IL-6 plasma levels reciprocally condition their effects on muscle function, all further analyses were performed stratified according to plasma IL-6 level.  Subjects with higher plasma IL-6 levels were older and, although the wide age range, had lower free IGF-I concentrations and lower total power and handgrip than subjects in the lowest category.

Furthermore, subjects with elevated plasma IL-6 levels had a greater BMI and higher IL-6 receptor and severity of insulin resistance than subjects in the lowest grouping. A significant association between IL-6, handgrip, and total power was found only in subjects in the third level of plasma IL-6 levels. In contrast, significant association of free IGF-I with handgrip and total power occurred only in subjects at the lowest plasma IL-6 level.  These findings suggest the existence of a relationship between IL-6 and IGF-I that reciprocally conditions their effect on muscle function.

Conclusions

This study provides evidence that higher plasma IL-6 levels and lower plasma IGF-I levels are associated with lower muscle strength and power. However, the reciprocal relationship between IL-6 and IGF-I in their joint effect on muscle function is more complex than previously understood.  The role of IL-6 in the development of disability in older persons has been documented widely. Elevated plasma IL-6 levels are associated with high mortality in the elderly, and higher plasma IL-6 levels are often found in older persons who are disabled in activities of daily living. It has been proposed that the high risk of disability associated with high IL-6 serum levels is explained by the catabolic effect of IL-6 on muscle, which results in accelerated sarcopenia. However, the true effect of IL-6 on muscle has not been investigated fully.  IL-6 plays a central role in the inflammatory response. In addition to its multiple effects at inflammation sites, IL-6 also induces the synthesis of the hepatic acute phase inflammation proteins, such as C-reactive protein, haptoglobin, and fibrinogen, while inhibiting the synthesis of others, such as IGF-I.

This study also explained a multifaceted relationship between plasma IL-6 and IGF-I that conditions the effect of these two mediators on muscle function. Based on the findings, and the literature, and in accordance with some literature, it is reasonable to hypothesize that a high level of inflammation, documented by high plasma IL-6 levels, might negatively affect muscle function through three different mechanisms as follows: 1) IL-6 directly affects muscle strength; 2) IL-6 inhibits the synthesis of IGF-I; and 3) IL-6 blocks the effect of IGF-I. These possibilities, although not definitively proved, are supported by the following findings of our study. 1) IL-6 was an independent predictor of handgrip and muscle power, especially in subjects with the highest level of plasma IL-6 levels, suggesting that the effect of IL-6 on muscle becomes important only above a certain threshold concentration.

The researchers’ findings may also shed light on the controversial results reported by previous studies that examined the relationship between IGF-I and muscle mass and function.  They believe further studies will be needed to confirm our findings in a longitudinal prospective and to gain insight into the pathophysiological mechanism by which IL-6 and IGF-I affect muscle function over the aging process.

Source: March 2003 edition American Journal of Physiology—Endocrinology and Metabolism, one of 14 journals published each month by the American Physiological Society (APS).

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.