Research Article: Symmetry and spatial distribution of muscle glucose uptake in the lower limbs during walking measured using FDG-PET

Date Published: April 29, 2019

Publisher: Public Library of Science

Author(s): Sjoerd Kolk, Edzo Klawer, Eric Visser, Daphne Lobeek, Jan Schepers, Nico Verdonschot, Vivian Weerdesteyn, Fabio A. Barbieri.


This study aimed to elucidate whether muscle activity (in terms of glucose uptake) between the legs can be considered symmetrical during walking. Furthermore, we aimed to determine whether the [18F]-fluorodeoxyglucose was distributed heterogeneously throughout each muscle, and if so, whether areas of high uptake would be clustered.

Ten healthy participants walked on a treadmill at self-selected comfortable walking speed for a total of 90 minutes, 60 minutes before and 30 minutes after intravenous injection of 50 MBq [18F]-fluorodeoxyglucose. Thereafter, a positron emission tomography/computed tomography scan of the lower limb was acquired. Three-dimensional muscle contours of 78 (= 39×2) muscles of the left and right lower limb were semi-automatically determined from magnetic resonance imaging scans. After non-rigid registration, those muscle contours were used to extract [18F]-fluorodeoxyglucose uptake from the positron emission tomography scans.

Large asymmetries were observed in the lower leg muscles (e.g. median absolute asymmetry index of 42% in the gastrocnemius medialis) and in the gluteus minimus (30% asymmetry) and gluteus medius (15% asymmetry), whereas the uptake in the thighs was relatively symmetrical between the limbs (<6% asymmetry). These were not related to limb-dominance nor to inter-limb differences in muscle volume. The [18F]-fluorodeoxyglucose distribution was not distributed normally; most voxels had a relatively low standardized uptake value, and a minority of voxels had a relatively high standardized uptake value. The voxels with higher [18F]-fluorodeoxyglucose uptake were distributed heterogeneously; they were clustered in virtually all muscles. The findings in this study challenge the common assumption of symmetry in muscle activity between the limbs in healthy subjects. The clustering of voxels with high uptake suggests that even in this prolonged repetitive task, different spatial regions of muscles contribute differently to walking than others.

Partial Text

Walking involves a complex integration of muscular contractions with the goal of maintaining stance stability and forward progression. Walking in healthy persons has traditionally been assumed to be a symmetrical motion, either from assumption or for convenience of data collection and analysis [1]. This assumption may be considered reasonable, as most healthy persons walk without a limp or other visible evidence of asymmetry. However, several studies have found that the legs and individual muscles do not necessarily behave symmetrically during gait. For instance, asymmetries in kinematics [2, 3] and muscle activation [4, 5] have been reported. In kinematics, Maupas et al. found that 51.6% of walkers exhibited more than 5° of angular difference in sagittal knee range of motion between the left and right knees [2]. Gundersen et al. found in 12 out of their 14 subjects that at least two examined parameters showed asymmetries (for example, maximum knee extension and step length), and that the asymmetries occurred in an unpredictable fashion between the dominant and non-dominant limbs [3]. In muscle activation (using electromyography), Õunpuu et al. found that nine out of ten subjects showed significant differences between the dominant and non-dominant limb in at least three out of seven muscles tested [4]. Arsenault et al. found between-limb differences in soleus activation of up to 20% of a maximum voluntary contraction [5]. A better understanding of these asymmetries is important, for instance in determining ranges of normal (healthy) asymmetry, beyond which a patient with a certain pathology is considered to be truly asymmetrical. Also, asymmetry is an important consideration in validating musculo-skeletal models, which generally assume that healthy persons walk with equal activity levels in muscles in both legs [6, 7].

The subjects, protocol and scans have been described in detail previously [23], and will therefore be described only briefly.

This study aimed to determine asymmetries in [18F]-fluorodeoxyglucose uptake between muscles in the dominant and the non-dominant lower limb, as well as to determine heterogeneities in [18F]-fluorodeoxyglucose uptake within muscles during walking, using three-dimensional magnetic resonance imaging-based whole-muscle segmentations. Large inter-limb differences in uptake were found in the lower leg muscles and in the gluteus medius and gluteus minimus (differences up to 98% were found), whereas the uptake in the thighs was relatively symmetrical between the limbs. Thus, our first hypothesis was rejected. [18F]-fluorodeoxyglucose uptake was not systematically higher in the dominant or the non-dominant limb in any muscle, including when inter-limb muscle volume differences were taken into account. The skew of the standardized uptake values was to the right almost exclusively, indicating that most voxels had a relatively low standardized uptake value, and that a minority of voxels had a relatively high standardized uptake value. Thus, our second hypothesis was confirmed. Finally, rather than being homogeneously distributed in the muscle, the voxels with high standardized uptake value tended to cluster in virtually all muscles, the clustering being strongest in the adductor magnus, the ankle plantar flexors, and the gluteus medius and minimus. Thus, our third hypothesis was rejected.

The volumetric analysis of [18F]-fluorodeoxyglucose uptake in both lower limbs after walking showed that muscle activity (in terms of glucose uptake) was symmetrical in the thigh muscles, whereas it was highly asymmetric in the lower leg and gluteal muscles in many subjects. These findings challenge the common assumption of symmetry between the limbs in healthy subjects. Practically all of the inter-subject differences disappeared when the results were averaged across subjects, which underlines that averaging individual subject data stemming from both limbs may preclude asymmetries from being noticed or reported. Studies that have the goal of validating muscle activation levels using subject-specific musculoskeletal models, will need to be cautious that muscle activity for the most active muscles during the activity (e.g. lower leg and gluteal muscles for walking) needs to be validated for each subject and each limb individually. As for the [18F]-fluorodeoxyglucose distribution within muscles, there was a majority of voxels that had a standardized uptake value that was lower than the mean standardized uptake value, and there was a minority of voxels with a relatively high standardized uptake value in almost all muscles. Those ‘hot’ voxels tended to cluster rather than being spread homogeneously throughout the muscle, but those clusters were not located in consistent locations in a given muscle across subjects. The inconsistent locations of ‘hot’ clusters highlights the added value of performing a three-dimensional analysis of uptake rather than examining uptake in only a single slice for each muscle. Future research could focus on revealing the relation of active versus resting [18F]-fluorodeoxyglucose uptake levels, on measuring kinematics and kinetics while the exercise is performed, and on combining the cumulative [18F]-fluorodeoxyglucose-positron emission tomography measurement with a temporal-sensitive method such as multi-channel electromyography. When applied in patients, FDG-PET offers the perspective of being able to show which muscles and which parts of muscles are activated less than ‘normal’, and which are more active and might be compensating for other muscles or for underlying pathology. This would be useful information that would be difficult to obtain through other methods. It could have benefit, for example, in studying patients who have undergone joint replacement, who have had an anterior cruciate ligament reconstruction, or who are suffering from neurological disease. Using [18F]-fluorodeoxyglucose-positron emission tomography to measure muscle activity remains an exciting new technique, which has the potential to further improve our understanding of muscle contributions during exercise in many ways, including in detecting differences in muscle activity levels between subjects, between limbs, and between regions within muscles.