Synopsis

Systemic inflammation has been shown to play a role in both the aging process and disease progression. However, the effect of inflammation on mitochondrial function has not been fully elucidated. We hypothesized that increased systemic inflammation, assessed through measurement of conventional markers of inflammation, would be accompanied by a decrease in mitochondrial function, as assessed by ³¹P MRS of leg muscle. Our results suggest that increased systemic inflammation may adversely affect mitochondrial function.

PURPOSE

EXPERIMENTAL DESIGN & METHODS

530 subjects from the Baltimore Longitudinal Study on Aging (BLSA) were studied: 241 males (mean age 70.75; range 24-91) and 289 females (mean age 69.92; age 24-98). Characteristics of the study population, including mean values of outcome measures, are shown in Table 1. ESR, CRP concentration, and IL-6 concentration were measured using standard laboratory techniques. ³¹P spectra of leg muscle were acquired using a 3T Achieva MR scanner (Philips, Best, The Netherlands). Subjects were supine, and a 10-cm ³¹P-tuned surface coil (PulseTeq, Surrey, UK) was fastened over the vastus lateralis muscle of the left thigh. A single-pulse sequence was employed with a 90° adiabatic excitation pulse followed by acquisition of 2048 points with a bandwidth of 2250 Hz, repetition time 1.5 s and four averages, resulting in a time resolution of 6 s. After collection of 9 resting spectra, subjects performed a knee extension exercise until the PCr peak height fell to 33% to 66% of its baseline value. Additional spectra were acquired during recovery, so that a total of 75 spectra were collected over 7.5 min. Spectra were processed using jMRUI (version 5.0).^7,8 The recovery rate of phosphocreatine, k_PCr =1/τ_PCr, was used as a metric of muscle oxidative phosphorylation capacity. k_PCr was determined by fitting the postexercise recovery of PCr to a mono-exponential function:

$$PCr(t) = PCr_{0} + ΔPCr\ (1- exp(-t/τ_{PCr}))$$

where PCr₀ is PCr peak area after completion of exercise, ΔPCr is the reduction in PCr peak area from baseline at end-exercise, and τ_PCr is the PCr exponential recovery time constant.⁶ We ensured accurate quantification of k_PCr through application of specific quality control criteria. Independent linear regression analyses were performed using RStudio to determine the relationship between k_PCr and each inflammatory marker, with quantitative results obtained after adjusting for age, sex, race, BMI and degree of PCr depletion.

RESULTS & DISCUSSION

Phosphocreatine recovery rate (k_PCr) was evaluated as a function of ESR (Fig. 1), CRP concentration (Fig. 2) and IL-6 concentration (Fig. 3), with a statistically significant inverse relationship being found for all three markers. These relationships persisted after adjustment for age as a confounding variable. The effect size was relatively small, indicating that, as expected, other factors also play a role in decreased k_PCr. However, the significant relationship between systemic inflammation is of great significance, since inflammation is a known correlate with the progression of aging and disease. For example, higher CRP levels are correlated with decreased muscle mass, independent of age and body composition,⁹ with similar findings observed for IL-6.¹⁰ In addition, systemic inflammation is negatively correlated with muscle function in specific pathologies; IL-6 is negatively correlated with exercise capacity and muscle strength in elderly subjects who have obstructive lung disease (OLD) as well as subjects without this diagnosis.¹¹ In addition, sarcopenic and sarcopenic-obese (SO) patients present with increased systemic inflammation that correlates with functional limitations.¹² Thus, systemic inflammation may play a central role in both normative and non-normative aging, and the correlation between inflammation and muscle bioenergetics provides a plausible basis for the attendant functional limitations.

CONCLUSIONS

ESR, CRP concentration, and IL-6 concentration are significantly associated with a decrease in muscle oxidative capacity as assessed by ³¹P MRS. These results, obtained on a normative population of healthy aging individuals, motivate additional investigation of the relationship between muscle bioenergetics and systemic inflammation in the setting of specific pathologies, especially those for which inflammation is a critical component.

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.

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