Previous research has shown that people with obesity, diabetes, and peripheral neuropathy have significantly greater amounts of intermuscular adipose tissue (IMAT) in the calf compared to a nonobese control group and that this calf IMAT was associated with poor physical performance [
It is also unknown whether calf IMAT accumulation is muscle or muscle compartment specific, that is, whether one muscle or a group of muscles tends to have more IMAT than others. Identifying preferential differences in IMAT accumulation may help to understand the purpose of IMAT. Muscles in the calf have different distributions of fast twitch and slow twitch fibers. For example, the gastrocnemius muscle is considered predominantly a fast twitch muscle and is used more for large force production, while the soleus muscle is considered more slow twitch and is a postural muscle that is better suited for using lipids as a fuel source [
Therefore, the purposes of this study were to determine if IMAT accumulation is muscle specific, that is, determine difference in IMAT volumes between individual muscles and muscle compartments, if calf IMAT is different between groups of healthy obese people (HO), a group with diabetes mellitus (D), and a group with diabetes and peripheral neuropathy (DN), if IMAT and/or the ratio of IMAT/muscle volume is related to function in these groups. We hypothesized that the soleus muscle would display more IMAT than the gastrocnemius muscle and all other calf compartments across the three groups due to the predominance of slow twitch fibers and higher lipid oxidation capacity in the soleus muscle. Additionally, we hypothesized that the D and DN groups would have greater volumes of IMAT in the calf, and similar calf muscle volumes compared to the HO group, and that the DN group would display the largest volume of calf IMAT of all 3 groups. We hypothesized that calf IMAT volume would be inversely correlated with measures of physical performance.
Forty-five subjects participated in this study (Table
Subject demographics by group. Values are means (SD).
Group | Gender (M/F) | Age (years) | BMI (kg/m2) | Weight (lbs) | Diabetes medication (oral only/insulin and oral) | HbA1c (%) | DM duration (years) | |
---|---|---|---|---|---|---|---|---|
HO | 10 | 4/6 | 64 (9) | 32.9 (4.6) | 213 (41) | NA | 5.8 (0.2) | NA |
D | 11 | 5/6 | 56 (9) | 35.5 (6.4) | 226 (33) | 6/5 | 8.1 (2.2) | 8.1 (6.9) |
DN | 24 | 15/9 | 64 (13) | 32.6 (6.3) | 217 (45) | 13/11 | 7.1 (1.3) | 12.9 (9.0) |
NA: not applicable.
Participants were recruited from the Washington University School of Medicine Diabetes Clinic, Washington University’s Volunteers for Health, the Center for Community Based Research, and from diabetes clinics in the surrounding St. Louis community. This study is part of a larger study investigating the effect of exercise for people with diabetes and peripheral neuropathy. Participant characteristics are listed in Table
Presence of peripheral neuropathy was determined based on both an inability to feel the 5.07 Semmes-Weinstein monofilament on at least one point on the plantar surface of the foot and on a vibration perception threshold greater than 25 V as measured with a biothesiometer applied to the plantar surface of the great toe [
Calf intermuscular adipose tissue volumes were quantified using MRI on the right leg of each participant. The MRI scans were performed with the participant in a supine position with a Siemens CP extremity coil placed over the right calf muscle. The MRI measurements were performed with a 3.0 Tessla superconducting magnet with a pulse sequence of
(a) MRI image of calf with bone removed. (b) Subcutaneous adipose tissue removed. (c) Calf divided into 5 compartments (anterior, lateral, deep, gastrocnemius, and soleus).
All participants performed the six-minute walk test [
The modified 9-item PPT was used to assess physical performance in all participants. This test is designed to mimic activities of daily living, and the 9-item PPT has been shown to correlate well with disability and frailty [
Stair power (in watts) was calculated based on the time it took each participant to climb a flight of 10 stairs as part of the PPT (average of 2 trials) using the following formula which was adapted from the stair sprinting power test [
Concentric isokinetic ankle dorsiflexor and plantarflexor peak torque and power were assessed using a Biodex Multijoint System 3 Pro isokinetic dynamometer. The tests were performed at angular velocities of 60°/s. The average power at 60°/s was determined by the time-averaged integrated area under the curve at the constant velocity of movement in the available range of motion [
Statistical analyses were performed using Systat for windows, version 13.0. An analysis of variance was used to examine the main and interaction effects of calf IMAT and muscle volumes (gastrocnemius, soleus, anterior compartment, lateral compartment, and deep compartment), group (HO, D, DN), and measures of physical performance. Post hoc
There were no group differences in age, BMI, or weight (
ANOVA results: muscle morphology measures; all values are means (SD) in cm3.
HO | D | DN | ||
---|---|---|---|---|
Muscle volume | 404 (90) | 434 (72) | 407 (88) | 0.65 |
IMAT volume | 67 (54) | 65 (36) | 70 (40) | 0.94 |
Anterior compartment muscle volume | 62 (9) | 69 (15) | 65 (14) | 0.57 |
Anterior compartment IMAT volume | 7 (5) | 10 (11) | 9 (5) | 0.53 |
Lateral compartment muscle volume | 36 (10) | 38 (9) | 37 (11) | 0.85 |
Lateral compartment IMAT volume | 6 (5) | 5 (3) | 7 (4) | 0.62 |
Deep compartment muscle volume | 51 (15) | 54 (13) | 60 (12) | 0.15 |
Deep compartment IMAT volume | 9 (6) | 8 (4) | 11 (5) | 0.23 |
Soleus muscle volume | 127 (28) | 130 (26) | 118 (32) | 0.46 |
Soleus IMAT volume | 14 (14) | 14 (8) | 15 (10) | 0.97 |
Gastroc. muscle volume | 128 (31) | 142 (27) | 122 (40) | 0.35 |
Gastroc. IMAT volume | 31 (28) | 27 (15) | 28 (21) | 0.90 |
IMAT/muscle volume | 0.144 (0.07) | 0.158 (0.11) | 0.193 (0.16) | 0.58 |
Anterior compartment: comprised of tibialis anterior, extensor digitorum longus, and extensor hallucis longus muscles.
Lateral compartment: comprised of peroneus longus and brevis muscles.
Deep compartment: comprised of the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles.
There were no group differences between any of the calf muscle or IMAT volume measures (Table
ANOVA results: physical performance measures. Values are means (SD).
HO | D | DN | ||
---|---|---|---|---|
DFPT (Nm) | 5.2 (4.3) | 15.3 (7.5)a | 4.5 (5.3) | 0.00 |
DFPOW (W) | 2.3 (2.4) | 9.8 (6.6)a | 2.2 (3.2) | 0.00 |
PFPT (Nm) | 58.0 (18.6) | 48.1 (13.0) | 51.4 (16.5) | 0.37 |
PFPOW (W) | 45.9 (15.1) | 38.7 (10.9) | 41.9 (18.1) | 0.38 |
6 MW (m) | 512.4 (48)a | 459.6 (80) | 425.5 (98) | 0.04 |
PPT | 34 (1.5) | 31 (2.4) | 28 (4.0) | 0.001* |
Stair power (W) | 808 (327) | 671 (163) | 601 (226) | 0.04* |
*Indicates all 3 groups are different.
aIndicates that the group is different from the other 2 groups.
DFPT: dorsiflexor peak torque; DFPOW: dorsiflexor power; PFPT: plantarflexor peak torque; PFPOW: plantarflexor power; 6 MW: six-minute walk distance; PPT: physical performance test (9 items).
Across all participants, calf IMAT volume was associated with BMI (
Correlation matrix.
IMAT vol | 6 MW | PPT | Stair POW | Muscle Vol | IMAT/Mus Vol | |
---|---|---|---|---|---|---|
BMI | 0.31* | −0.18 | 0.01 | 0.21 | 0.49* | 0.08 |
IMAT vol | −0.47* | −0.36* | −0.18 | −0.32* | 0.93* | |
6 MW | 0.79* | 0.58* | 0.25 | −0.48* | ||
PPT | 0.60* | 0.24 | −0.44* | |||
Stair Pow | 0.51* | −0.30* | ||||
Muscle vol | −0.35* |
*Indicates significance (
IMAT: intermuscular adipose tissue volume; 6 MW: six-minute walk distance; PPT: physical performance test (9 items); Stair Pow: stair power; Muscle Vol: calf muscle volume; IMAT/MusVol: ratio of IMAT/muscle volume in the calf.
This study is the first to report that the amount of IMAT/muscle volume in the calf is muscle and compartment specific in the pathologies of obesity, diabetes, and diabetes combined with peripheral neuropathy. The gastrocnemius muscle had the largest ratio of IMAT/muscle volume compared to any of the calf muscles and compartments, which was contrary to what we expected and to what has been reported in obese animal models [
Overall, the inverse correlation between calf IMAT volume and physical performance indicates that IMAT accumulation is associated with physical performance decline, but it appears that there are other factors, such as the presence of diabetes and/or neuropathy, that are key mediators of physical performance. The ratio of IMAT/muscle volume was inversely related to measures of muscle performance across all subjects. The ratio of calf IMAT/muscle volume may be an indicator of physical performance, but the IMAT/Muscle volume does not differ between those with diabetes and diabetes and neuropathy compared to a healthy obese group of subjects. These results are consistent with other reports in the literature and suggest measures other than absolute muscle volume or muscle cross-sectional area are needed to completely characterize calf muscle composition and muscle performance [
We found, contrary to our expectations, that there were no group differences in measures of IMAT volumes or muscle volumes between a group with HO, a group with D, and a group with DN. These results indicate that diabetes and peripheral neuropathy were not associated with IMAT accumulation in the calf beyond their association with BMI in these groups of subjects. These results were surprising because our previous study indicated that a group with obesity, diabetes, and peripheral neuropathy had two times the volume of IMAT compared to a nonobese, nondiabetic, nonneuropathic control group [
Of note, the HO group had an average HbA1c value of 5.8 which is indicative of people at risk for developing diabetes [
There are limitations that should be considered. First, we have a relatively small sample size. Based on the small effect size between groups, a post hoc power analysis revealed that we would need to collect data on more than 3600 individuals to be powered to find group differences in total IMAT in the calf with a power of 0.80 and an alpha level at 0.05. The magnitude and impact of IMAT accumulation in specific calf muscles or compartments in people with severe diabetes and peripheral neuropathy requires additional investigation. We are limited in our ability to interpret results because we do not have biopsies or other biochemical measures of the individual muscles or adipose tissues to further elucidate characteristics beyond our macroscopic MRI measures. This study is also limited in that we do not have a measure of activity level for each participant, so it is possible that our groups could be different from each other in levels of activity. Future studies should characterize subjects on activity level, activity types (endurance versus strengthening exercise), and neuropathy severity to enhance interpretation of results. We do not have electrodiagnostic measures of neuropathy, and it possible that electrodiagnostic measures would have provided us with a more accurate measure of neuropathy severity including a measure of subclinical neuropathy in the D or HO groups. Since the group with DN was originally recruited for an exercise study, it is possible that we have a selection bias towards people with DN who are higher functioning. In addition, this group only had 2 people with a history of plantar foot ulcer, so we do not believe these results are generalizable to people with more severe complications and longer durations of diabetes and peripheral neuropathy. Lastly, the correlations between the different variables only indicate association and cannot determine cause and effect.
In conclusion, this study found that increased calf IMAT volume accumulation was muscle specific; the gastrocnemius muscle had the largest ratio of IMAT/muscle volume of all of the calf muscles and compartments. In addition, calf IMAT was associated with poorer physical performance. The groups with D and DN had lower measures of physical performance than the HO group, suggesting that more severe impairment in metabolic pathology, along with IMAT accumulation, impacts physical performance.
The authors deny any conflict of interests present in this work.
This work was supported by grant funding from NIH NCMRR R21 HD058938 (to M. J. Mueller), T32 HD007434-14 (to M. J. Mueller and L. J. Tuttle), NSMRC R24HD650837, NIH UL1 RR024992, and scholarships from the Foundation for Physical Therapy (to L. J. Tuttle).