Alteration of skeletal muscle energy metabolism assessed by 31 P MRS in clinical routine: Part 2. Clinical application.

In this second part of a two-part paper, we intend to demonstrate the impact of the previously proposed advanced quality control pipeline. To understand its benefit and challenge the proposed methodology in a real scenario, we chose to compare the outcome when applying it to the analysis of two patient populations with significant but highly different types of fatigue: COVID-19 and multiple sclerosis (MS). 31 P-MRS was performed on a 3 T clinical MRI, in 19 COVID-19 patients, 38 MS patients, and 40 matched healthy controls. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Long and short TR acquisitions were also made at rest for T1 correction. The advanced data quality control pipeline presented in Part 1 is applied to the selected patient cohorts to investigate its impact on clinical outcomes. We first used power and sample size analysis to estimate objectively the impact of adding the quality control score (QCS). Then, comparisons between patients and healthy control groups using the validated QCS were performed using unpaired t tests or Mann-Whitney tests (p < 0.05). The application of the QCS resulted in increased statistical power, changed the values of several outcome measures, and reduced variability (standard deviation). A significant difference was found between the T1PCr and T1Pi values of MS patients and healthy controls. Furthermore, the use of a fixed correction factor led to systematically higher estimated concentrations of PCr and Pi than when using individually corrected factors. We observed significant differences between the two patient populations and healthy controls for resting [PCr]-MS only, [Pi ], [ADP], [H2 PO4 - ], and pH-COVID-19 only, and post-exercise [PCr], [Pi ], and [H2 PO4 - ]-MS only. The dynamic indicators τPCr , τPi , ViPCr , and Vmax were reduced for COVID-19 and MS patients compared with controls. Our results show that QCS in dynamic 31 P-MRS studies results in smaller data variability and therefore impacts study sample size and power. Although QCS resulted in discarded data and therefore reduced the acceptable data and subject numbers, this rigorous and unbiased approach allowed for proper assessment of muscle metabolites and metabolism in patient populations. The outcomes include an increased metabolite T1 , which directly affects the T1 correction factor applied to the amplitudes of the metabolite, and a prolonged τPCr , indicating reduced muscle oxidative capacity for patients with MS and COVID-19.

Alteration of skeletal muscle energy metabolism assessed by phosphorus-31 magnetic resonance spectroscopy in clinical routine, part 1: Advanced quality control pipeline.

Implementing a standardized phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) dynamic acquisition protocol to evaluate skeletal muscle energy metabolism and monitor muscle fatigability, while being compatible with various longitudinal clinical studies on diversified patient cohorts, requires a high level of technicality and expertise. Furthermore, processing data to obtain reliable results also demands a great degree of expertise from the operator. In this two-part article, we present an advanced quality control approach for data acquired using a dynamic 31 P-MRS protocol. The aim is to provide decision support to the operator to assist in data processing and obtain reliable results based on objective criteria. We present here, in part 1, an advanced data quality control (QC) approach of a dynamic 31 P-MRS protocol. Part 2 is an impact study that will demonstrate the added value of the QC approach to explore data derived from two clinical populations that experience significant fatigue, patients with coronavirus disease 2019 and multiple sclerosis. In part 1, 31 P-MRS was performed using 3-T clinical MRI in 175 subjects from clinical and healthy control populations conducted in a University Hospital. An advanced data QC score (QCS) was developed using multiple objective criteria. The criteria were based on current recommendations from the literature enriched by new proposals based on clinical experience. The QCS was designed to indicate valid and corrupt data and guide necessary objective data editing to extract as much valid physiological data as possible. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Using QCS enabled rapid identification of subjects with data anomalies, allowing the user to correct the data series or reject them partially or entirely, as well as identify fully valid datasets. Overall, the use of the QCS resulted in the automatic classification of 45% of the subjects, including 58 participants who had data with no criterion violation and 21 participants with violations that resulted in the rejection of all dynamic data. The remaining datasets were inspected manually with guidance, allowing acceptance of full datasets from an additional 80 participants and recovery phase data from an additional 16 subjects. Overall, more anomalies occurred with patient data (35% of datasets) compared with healthy controls (15% of datasets). In conclusion, the QCS ensures a standardized data rejection procedure and rigorous objective analysis of dynamic 31 P-MRS data obtained from patients. This methodology contributes to efforts made to standardize 31 P-MRS practices that have been underway for a decade, with the goal of making it an empowered tool for clinical research.

Statistical Models to Assess Leg Muscle Mass in Ambulatory Children With Spastic Cerebral Palsy Using Dual-Energy X-Ray Absorptiometry.

Cerebral palsy (CP) is a movement disorder associated with small and weak muscles. Methods that accurately assess muscle mass in children with CP are scarce. The purpose of this study was to determine whether dual-energy X-ray absorptiometry (DXA) accurately estimates midleg muscle mass in ambulatory children with spastic CP. Ambulatory children with spastic CP and typically developing children 5-11 y were studied (n = 15/group). Fat-free soft tissue mass (FFST) and fat mass at the middle third of the tibia (i.e., midleg) were estimated using DXA. Muscle mass (muscleMRI) and muscle mass corrected for intramuscular fat (muscleMRIfc) in the midleg were estimated using magnetic resonance imaging (MRI). Statistical models were created to predict muscleMRI and muscleMRIfc using DXA. Children with CP compared to typically developing children had lower FFST (38%), muscleMRI (40%) and muscleMRIfc (47%) (all p < 0.05) and a lower ratio of muscleMRIfc to FFST (17%, p < 0.05). DXA-based models developed using data from typically developing children overestimated muscleMRI (13%) and muscleMRIfc (22%) (both p < 0.05) in children with CP. DXA-based models developed using data from children with CP explained 91% of the variance in muscleMRI and 90% of the variance in muscleMRIfc in children with CP (both p < 0.05). Moreover, the estimates were not different from muscleMRI and muscleMRIfc (both p > 0.99). We conclude that DXA-based statistical models accurately estimate midleg muscle mass in children with CP when the models are composed using data from children with CP rather than typically developing children.

Femoral cartilage ultrasound echo-intensity is a valid measure of cartilage composition.

This study aimed to create a conversion equation that accurately predicts cartilage magnetic resonance imaging (MRI) T2 relaxation times using ultrasound echo-intensity and common participant demographics. We recruited 15 participants with a primary anterior cruciate ligament reconstruction between the ages of 18 and 35 years at 1-5 years after surgery. A single investigator completed a transverse suprapatellar scan with the ACLR limb in max knee flexion to image the femoral trochlea cartilage. A single reader manually segmented the femoral cartilage cross-sectional area to assess the echo-intensity (i.e., mean gray-scale pixel value). At a separate visit, a T2 mapping sequence with the MRI beam set to an oblique angle was used to image the femoral trochlea cartilage. A single reader manually segmented the cartilage cross-sectional area on a single MRI slice to assess the T2 relaxation time. A stepwise, multiple linear regression was used to predict T2 relaxation time from cartilage echo-intensity and common demographic variables. We created a conversion equation using the regression betas and then used an ICC and Bland-Altman plot to assess agreement between the estimated and true T2 relaxation time. Cartilage ultrasound echo-intensity and age significantly predicted T2 relaxation time (F = 7.33, p = 0.008, R2 = 0.55). When using the new conversion equation to estimate T2 relaxation time from cartilage echo-intensity and age, there was strong agreement between the estimated and true T2 relaxation time (ICC2,k = 0.84). This study provides promising preliminary data that cartilage echo-intensity combined with age can be used as a clinically accessible tool for evaluating cartilage composition.

Reliability of blood pressure responses used to define an exaggerated blood pressure response to exercise in young healthy adults.

Exaggerated blood pressure (BP) responses (EBPR) to exercise are prognostic of future cardiovascular risk. The primary objective of this study was to assess the test-retest reliability of BP responses used to categorize EBPR as absent or present. Twenty-seven healthy adults [21(2) years; 12 males] with resting BP < 130/80 mmHg completed a modified Bruce protocol treadmill exercise test on two visits separated by 6 (3) days. BP measurements were obtained during exercise using an automated auscultatory device. Submaximal and maximal systolic and diastolic BP, the change in diastolic BP from rest to maximal diastolic BP, and the change in systolic BP relative to the change in exercise intensity, quantified using the metabolic equivalent of task (SBP/MET-slope) were determined. Test-retest reliability of these BP responses was assessed using intraclass correlation coefficients (ICC) with a value ≥0.61 considered as substantial reliability. Submaximal diastolic BP demonstrated substantial reliability in the total group (ICC = 0.670; P ≤ 0.001). In males, submaximal systolic BP (ICC = 0.655, P < 0.01), submaximal diastolic BP (ICC = 0.699; P < 0.01) and maximal systolic BP (ICC = 0.794; P ≤ 0.001) demonstrated substantial reliability. All other BP responses were not reliable. Despite the prognostic value of EBPR, only three BP responses used to categorize EBPR demonstrated substantial test-retest reliability in healthy young males. In clinical practice, these preliminary findings would support the use of exercise BPs to identify young males with elevated cardiovascular risk, but additional research is needed to improve the clinical utility of exercise BPs and EBPR in females.

Rectus Femoris Ultrasound Echo Intensity Is a Valid Estimate of Percent Intramuscular Fat in Patients Following Anterior Cruciate Ligament Reconstruction.

OBJECTIVE: The aim of the work described here was to evaluate quadriceps muscle ultrasound metrics and common demographic variables to create a conversion equation that validly predicts magnetic resonance imaging (MRI) percent intramuscular fat after anterior cruciate ligament reconstruction (ACLR). METHODS: We recruited 15 participants between the ages of 18 and 35 y who were 1-5 y post-ACLR. For the MRI assessment, we used an iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) sequence to assess the mid-thigh. A single reader manually segmented the rectus femoris on two consecutive MRI slices using ITK-Snap to estimate the percent intramuscular fat. For the ultrasound assessment, a single investigator captured transverse panoramic ultrasound images of the mid-thigh with the participant positioned supine and the knee flexed to 30°. A separate single reader used ImageJ to manually segment the rectus femoris ultrasound images. Ultrasound metrics included muscle cross-sectional area, echo intensity and subcutaneous fat thickness. A stepwise linear multiple regression was used to develop an equation to predict MRI percent intramuscular fat using the ultrasound metrics and common demographics (i.e., age, sex, height, mass). Additionally, intraclass correlation coefficients (ICC2,k) and Bland-Altman plots were used to assess the agreement between true and estimated percent intramuscular fat. RESULTS: Echo intensity and age significantly predicted MRI intramuscular fat percent (p = 0.003, r2 = 0.62). When using the conversion equation, there was high agreement (ICC2,k = 0.87, 95% confidence interval: 0.62-0.96) between the estimated and true percent intramuscular fat. CONCLUSION: Our patient population-specific conversion equation that uses quadriceps muscle ultrasound echo intensity and age is a valid estimate of MRI percent intramuscular fat.

The Effect of Downhill Running on Quadriceps Muscle in Growth-Restricted Mice.

INTRODUCTION: Growth restriction (GR) reduces ribosome abundance and skeletal muscle mass in mice. A reduction in skeletal muscle mass increases the risk of frailty and is associated with high morbidity and mortality rates. As eccentric type exercise increases muscle mass, this investigation aimed to determine if eccentric loading of skeletal muscle via downhill running (DHR) increased muscle mass in GR mice. METHODS: Mice were growth-restricted either gestational undernutrition (GUN, n = 8 litters), postnatal undernutrition (PUN, n = 8 litters), or were not restricted (CON, n = 8 litters) via a validated cross-fostering nutritive model. On postnatal day (PN) 21, all mice were weaned to a healthy diet, isolating the period of GR to early life as seen in humans. At PN45, mice were assigned to either a DHR (CON, n = 4 litters; GUN, n = 4 litters; PUN, n = 4 litters) or sedentary (SED: CON, n = 4 litters; GUN, n = 4 litters; PUN, n = 4 litters) group. Downhill running (16% decline: 18 m·min -1 ) was performed in 30-min bouts, three times per week, for 12 wk on a rodent treadmill. At PN129, the quadriceps femoris was dissected and evaluated for mass, myofiber size and type, and molecular markers of growth. RESULTS: Following training, CON-DHR mice having larger cells than CON-SED, GUN-SED, PUN-SED, and PUN-DHR mice ( P < 0.05). The PUN group (as compared with CON) had reduced body mass ( P < 0.001), upstream binding factor abundance ( P = 0.012), phosphor-mTOR ( P < 0.001), and quadriceps mass ( P = 0.02). The GUN and PUN groups had increased MuRF1 abundance ( P < 0.001) compared with CON ( P < 0.001). CONCLUSIONS: The blunted response to training suggests GR mice may have anabolic resistance when exposed to eccentric type exercise.

The impact of statin therapy and aerobic exercise training on skeletal muscle and whole-body aerobic capacity.

BACKGROUND: Statin use is widely recognized for improving cardiovascular health, but questions remain on how statin use influences skeletal muscle, particularly mitochondrial function. STUDY OBJECTIVE DESIGN AND PARTICIPANTS: The influence of statin therapy and exercise (EX) on aerobic capacity was determined. In Study1, skeletal muscle aerobic capacity was measured before and after 80 mg atorvastatin therapy. In Study2, aerobic capacity (skeletal muscle and whole body) was measured before and after a 12-week exercise randomized control trial in older adults (age = 67 ± 5 yrs.), a subset of which were on chronic low-moderate intensity statin therapy. MAIN OUTCOME MEASURES: Muscle oxidative capacity was determined from the phosphocreatine recovery rate constant (kPCr) using 31P Magnetic Resonance Spectroscopy. Whole body peak oxygen uptake (VO2 peak) was measured during a graded exercise test with indirect calorimetry. RESULTS: High dose statin therapy resulted in a 12% reduction in muscle oxidative capacity (pre = 1.34 ± 0.34 min-1, post = 1.17 ± 0.25 min-1, p = 0.004). Similarly, chronic low-moderate dose statin therapy was associated with lower muscle oxidative capacity at baseline (1.50 ± 0.35 min-1) compared to non-statin users (1.88 ± 0.047 min-1, p = 0.019). Following EX, muscle oxidative capacity increased by 35-40% (statin: Pre: 1.39 ± 0.44 vs. Post: 1.88 ± 0.47 min-1, no statin Pre: 1.86 ± 0.58 vs. Post: 2.58 ± 0.85 min-1) compared to control groups (Pre: 1.74 ± 0.27 vs Post: 1.75 ± 0.49 min-1, p = 0.001). VO2 peak increased by 11% for EX groups (Pre: 18.8 ± 2.8 vs. Post: 20.8 ± 3.0 ml·kg-1·min-1) following training compared to a small decline in controls (Pre: 21.8 ± 3.7 vs. Post: 20.8 ± 3.04 ml·kg-1·min-1, p = 0.001). CONCLUSIONS: Statin therapy resulted in reduced muscle oxidative capacity. Aerobic exercise improved skeletal muscle oxidative capacity and whole-body aerobic capacity during statin therapy.

Lower extremity MRI following 10-week supervised exercise intervention in patients with diabetic peripheral neuropathy.

INTRODUCTION: The purpose of this study was to characterize using MRI the effects of a 10-week supervised exercise program on lower extremity skeletal muscle composition, nerve microarchitecture, and metabolic function in individuals with diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS: Twenty participants with DPN completed a longitudinal trial consisting of a 30-day control period, during which subjects made no change to their lifestyle, followed by a 10-week intervention program that included three supervised aerobic and resistance exercise sessions per week targeting the upper and lower extremities. The participants' midcalves were scanned with multinuclear MRI two times prior to intervention (baseline1 and baseline2) and once following intervention to measure relaxation times (T1, T1ρ, and T2), phosphocreatine recovery, fat fraction, and diffusion parameters. RESULTS: There were no changes between baseline1 and baseline2 MRI metrics (p>0.2). Significant changes (p<0.05) between baseline2 and postintervention MRI metrics were: gastrocnemius medialis (GM) T1 -2.3%±3.0% and soleus T2 -3.2%±3.1%. Trends toward significant changes (0.050.3) and tibial nerve fractional anisotropy (p>0.6) and apparent diffusion coefficient (p>0.4). CONCLUSIONS: The 10-week supervised exercise intervention program successfully reduced adiposity and altered resting tissue properties in the lower leg in DPN. Gastrocnemius mitochondrial oxidative capacity and tibial nerve microarchitecture changes were not observed, either due to lack of response to therapy or to lack of measurement sensitivity.

Brain activation during interference resolution in young and older adults: an fMRI study.

A rapid event-related fMRI arrow flanker task was used to study aging-associated decline in executive functions related to interference resolution. Older adults had more difficulty responding to Incongruent cues during the flanker task compared to the young adults; the response time difference between the Incongruent and Congruent conditions in the older group was over 50% longer compared to the young adults. In the frontal regions, differential activation ("Incongruent-Congruent" conditions) was observed in the inferior and middle frontal gyri in within-group analyses for both groups. However, the cluster was smaller in the older group and the centroid location was shifted by 19.7 mm. The left superior and medial frontal gyri also appeared to be specifically recruited by older adults during interference resolution, partially driven by errors. The frontal right lateralization found in the young adults was maintained in the older adults during successful trials. Interestingly, bilateral activation was observed when error trials were combined with successful trials highlighting the influence of brain activation associated with errors during cognitive processing. In conclusion, aging appears to result in modified functional regions that may contribute to reduced interference resolution. In addition, error processing should be considered and accounted for when studying age-related cognitive changes as errors may confound the interpretation of task specific age-related activation differences.

Quantifying bone marrow fat using standard T1-weighted magnetic resonance images in children with typical development and in children with cerebral palsy.

Excess bone marrow adiposity may have a negative effect on bone growth and development. The aim of this study was to determine whether a procedure using standard T1-weighted magnetic resonance images provides an accurate estimate of bone marrow fat in children with typical development and in children with mild spastic cerebral palsy (CP; n = 15/group; 4-11 y). Magnetic resonance imaging was used to acquire T1-weighted images. It was also used to acquire fat and water images using an iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) technique. Bone marrow fat volume and fat fraction in the middle-third of the tibia were determined using the standard T1-weighted images (BMFVT1 and BMFFT1, respectively) and the fat and water images (BMFVIDEAL and BMFFIDEAL, respectively). In both groups, BMFVT1 was highly correlated with (both r > 0.99, p < 0.001) and not different from (both p > 0.05) BMFVIDEAL. In both groups, BMFFT1 was moderately correlated with (both r = 0.71, p < 0.01) and not different from (both p > 0.05) BMFFIDEAL. There was no group difference in BMFVT1 or BMFVIDEAL (both p > 0.05). BMFFIDEAL was higher in children with CP (p < 0.05), but there was no group difference in BMFFT1 (p > 0.05). We conclude that a procedure using standard T1-weighted magnetic resonance images can produce estimates of bone marrow fat volume similar to estimates from the IDEAL technique in children. However, it is less sensitive to variation in the bone marrow fat fraction.

The postprandial increase in blood triglycerides has no direct effect on the brain BOLD response.

A previous study showed that ingestion of a liquid meal high in polyunsaturated lipids decreased the blood-oxygenation-level-dependent (BOLD) response measured by functional magnetic resonance imaging (fMRI) during a finger-tapping motor task, and suggested that this effect was due to a direct effect of blood lipids on the cerebral vasculature. This study compared the time course and magnitude of the BOLD response in fixed anatomic locations before and 3 h after ingestion of high versus low lipid content liquid meals (235 ml Ensure Plus [Abbot Labs] with or without 50 ml added canola oil). Blood triglyceride content peaked 3 h after the high lipid meal and was elevated by 33% compared with the low lipid meal. There was no significant effect of meal composition on the time course or magnitude of the BOLD response in fixed-location clusters of voxels which were activated during either a motor (finger-tapping), a visual (flashing checkerboard), or an integrative/cognitive (number addition) block-design task paradigm. The results indicate that increased blood total triglyceride content after a meal with relatively high polyunsaturated fat does not directly alter the hemodynamic BOLD response to neural activity. However, the postprandial effect on BOLD response of other meals with varying fat types and amounts, as well as other nutrients and phytochemicals, remains to be determined.

Comparison of oxidative capacity among leg muscles in humans using gated 31P 2-D chemical shift imaging.

In many small animals there are distinct differences in fiber-type composition among limb muscles, and these differences typically correspond to marked disparities in the oxidative capacities. However, whether there are similar differences in the oxidative capacity among leg muscles in humans is less clear. The purpose of this study was to compare the rate of phosphocreatine (PCr) recovery, a functional in vivo marker of oxidative capacity, in the lateral and medial gastrocnemius, soleus, and the anterior compartment of the leg (primarily the tibialis anterior) of humans. Subjects performed plantar flexion and dorsiflexion gated exercise protocols consisting of 70 sets of three rapid dynamic contractions (<2.86 s) at 20 s intervals (total: 23.3 min). Starting after the sixth set of contractions, (31)P 2-D CSI (8 x 8 matrix, 14-16 cm FOV, 3 cm slice, TR 2.86 s) were acquired via a linear transmit/receive surface coil using a GE 3T Excite System. The CSI data were zero-filled (32 x 32) and a single FID was produced for each time point in the lateral and medial gastrocnemius, soleus, and anterior compartment. The time constant for PCr recovery was calculated from tau = -Deltat/ln[D/(D + Q)], where Q is the percentage change in PCr due to contraction during the steady-state portion of the protocol, D the additional drop in PCr from rest, and Deltat is the interval between contractions. The tau of PCr recovery was longer (p < 0.05) in the anterior compartment (32 +/- 3 s) than in the lateral (23 +/- 2 s) and medial gastrocnemius muscles (24 +/- 3 s) and the soleus (22 +/- 3 s) muscles. These findings suggest that the oxidative capacity is lower in the anterior compartment than in the triceps surae muscles and is consistent with the notion that fiber-type phenotypes vary among the leg muscles of humans.

Aerobic Exercise Improves Microvascular Function in Older Adults.

Microvascular function is reduced with age, disease, and inactivity. Exercise is well known to improve vascular health and has the potential to improve microvascular function in aging and disease. PURPOSE: The study aimed to assess changes in peripheral microvascular function in sedentary older adults after aerobic exercise training. METHODS: Twenty-three sedentary older adults (67 ± 5 yr, body mass index = 29 ± 5, mean ± SD) successfully completed a randomized 12-wk graded treadmill walking intervention. The exercise group (EX) performed 40 min of uphill walking 4 d·wk at 70% heart rate reserve. The control group (CON) maintained a sedentary lifestyle for 12 wk. Blood oxygen level-dependent (BOLD) responses of the soleus measured by magnetic resonance imaging were used to evaluate microvascular function; brief (1 s) maximal plantarflexion contractions were performed. Separately, blood flow in the popliteal artery was measured by ultrasound after brief contraction. Phosphorus magnetic resonance spectroscopy of the calf was used to examine muscle oxidative capacity, and whole-body peak oxygen consumption (V˙O2peak) was used to confirm training-induced cardiorespiratory adaptations. RESULTS: Peak postcontraction BOLD response increased by 33% in EX (PRE, 3.3% ± 1.0%; POST, 4.4% ± 1.4%) compared with CON (PRE, 3.0% ± 1.3%; POST, 3.2% ± 1.5%), P < 0.05. EX with hypertension tended to show a blunted peak BOLD increase (n = 6, 15%) compared with EX normotensive (n = 7, 50%), P = 0.056. Peak postcontraction blood flow increased by 39% in EX (PRE, 217 ± 88 mL·min; POST, 302 ± 167 mL·min) compared with CON (PRE, 188 ± 54 mL·min; POST, 184 ± 44 mL·min), P < 0.05. EX muscle oxidative capacity (kPCr) improved by 40% (PRE, 1.60 ± 0.57 min; POST, 2.25 ± 0.80 min) compared with CON (PRE, 1.69 ± 0.28 min; POST, 1.76 ± 0.52 min), P < 0.05. V˙O2peak increased by 9% for EX (PRE, 19.0 ± 3.1 mL·kg·min; POST, 20.8 ± 2.9 mL·kg·min) compared with a 7% loss in CON (PRE, 21.9 ± 3.6 mL·kg·min; POST, 20.4 ± 3.5 mL·kg·min), P < 0.05. CONCLUSION: Moderate aerobic exercise significantly improved microvascular function of the leg in older adults.

Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy.

PURPOSE: The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments. METHODS: This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future. FINDINGS: Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention. IMPLICATIONS: Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.

Age Reduces Microvascular Function in the Leg Independent of Physical Activity.

The microvasculature is critical in the control of blood flow. Aging and reduced physical activity (PA) may both decrease microvascular function. PURPOSE: The primary aim was to evaluate the influence of age on microvascular function in adults with similar PA levels. Secondary aims were to assess the reliability of muscle functional magnetic resonance imaging in older adults (OA) and the relationship between PA and microvascular function in OA. METHODS: Microvascular blood-oxygen-level dependent (BOLD) responses were measured in young adults (YA, n = 12, mean ± SD age = 21 ± 1 yr old, PA = 239 ± 73 × 10 counts per day) and OA (n = 13, 64 ± 4 yr old, PA = 203 ± 48 × 10 counts per day). Functional magnetic resonance images (3T, echo planar BOLD) of the leg were acquired after brief (1 s) maximal voluntary isometric contractions. The test-retest reliability of BOLD responses and the Pearson correlation between peak BOLD and PA were assessed in a group of OA (OA-r) with a broad range of PA (66 ± 5 yr old, n = 9, PA range = 54 × 10 to 674 × 10 counts per day). RESULTS: Peak BOLD microvascular responses were reduced for OA compared with YA. OA peak BOLD was 27% lower in the soleus (3.3% ± 0.8% OA vs 4.5% ± 1.4% YA; P = 0.017) and 40% lower in the anterior compartment (1.6% ± 0.6% OA vs 2.7% ± 1.1% YA; P = 0.006). Coefficients of variation were 8.6% and 11.8% for peak BOLD in the soleus and anterior compartment, respectively, with an intraclass correlation of 0.950 for both muscle regions. The correlation between peak BOLD and PA was r ≥ 0.715, P ≤ 0.030. CONCLUSIONS: Aging was associated with reduced microvascular function in leg muscles, independent of PA. The findings also revealed good reliability for BOLD magnetic resonance imaging in OA for the soleus and anterior compartment muscles.

Cortical bone deficit and fat infiltration of bone marrow and skeletal muscle in ambulatory children with mild spastic cerebral palsy.

INTRODUCTION: Nonambulatory children with severe cerebral palsy (CP) have underdeveloped bone architecture, low bone strength and a high degree of fat infiltration in the lower extremity musculature. The present study aims to determine if such a profile exists in ambulatory children with mild CP and if excess fat infiltration extends into the bone marrow. MATERIALS AND METHODS: Ambulatory children with mild spastic CP and typically developing children (4 to 11years; 12/group) were compared. Magnetic resonance imaging was used to estimate cortical bone, bone marrow and total bone volume and width, bone strength [i.e., section modulus (Z) and polar moment of inertia (J)], and bone marrow fat concentration in the midtibia, and muscle volume, intermuscular, subfascial, and subcutaneous adipose tissue (AT) volume and intramuscular fat concentration in the midleg. Accelerometer-based activity monitors worn on the ankle were used to assess physical activity. RESULTS: There were no group differences in age, height, body mass, body mass percentile, BMI, BMI percentile or tibia length, but children with CP had lower height percentile (19th vs. 50th percentile) and total physical activity counts (44%) than controls (both p<0.05). Children with CP also had lower cortical bone volume (30%), cortical bone width in the posterior (16%) and medial (32%) portions of the shaft, total bone width in the medial-lateral direction (15%), Z in the medial-lateral direction (34%), J (39%) and muscle volume (39%), and higher bone marrow fat concentration (82.1±1.8% vs. 80.5±1.9%), subfascial AT volume (3.3 fold) and intramuscular fat concentration (25.0±8.0% vs. 16.1±3.3%) than controls (all p<0.05). When tibia length was statistically controlled, all group differences in bone architecture, bone strength, muscle volume and fat infiltration estimates, except posterior cortical bone width, were still present (all p<0.05). Furthermore, a higher intermuscular AT volume in children with CP compared to controls emerged (p<0.05). CONCLUSIONS: Ambulatory children with mild spastic CP exhibit an underdeveloped bone architecture and low bone strength in the midtibia and a greater infiltration of fat in the bone marrow and surrounding musculature compared to typically developing children. Whether the deficit in the musculoskeletal system of children with CP is associated with higher chronic disease risk and whether the deficit can be mitigated requires further investigation.

Oxygen cost of dynamic or isometric exercise relative to recruited muscle mass.

BACKGROUND: Oxygen cost of different muscle actions may be influenced by different recruitment and rate coding strategies. The purpose of this study was to account for these strategies by comparing the oxygen cost of dynamic and isometric muscle actions relative to the muscle mass recruited via surface electrical stimulation of the knee extensors. METHODS: Comparisons of whole body pulmonary delta VO2 were made in seven young healthy adults (1 female) during 3 minutes of dynamic or isometric knee extensions, both induced by surface electrical stimulation. Recruited mass was quantified in T2 weighted spin echo magnetic resonance images. RESULTS: The delta VO2 for dynamic muscle actions, 242 +/- 128 ml x min(-1) (mean +/- SD) was greater (p = 0.003) than that for isometric actions, 143 +/- 99 ml x min(-1). Recruited muscle mass was also greater (p = 0.004) for dynamic exercise, 0.716 +/- 282 versus 0.483 +/- 0.139 kg. The rate of oxygen consumption per unit of recruited muscle (VO2(RM)) was similar in dynamic and isometric exercise (346 +/- 162 versus 307 +/- 198 ml x kg(-1) x min(-1); p = 0.352), but the VO2(RM) calculated relative to initial knee extensor torque was significantly greater during dynamic exercise 5.1 +/- 1.5 versus 3.6 +/- 1.6 ml x kg(-1) x Nm(-1) x min(-1) (p = 0.019). CONCLUSION: These results are consistent with the view that oxygen cost of dynamic and isometric actions is determined by different circumstances of mechanical interaction between actin and myosin in the sarcomere, and that muscle recruitment has only a minor role.

Deteriorated geometric structure and strength of the midfemur in men with complete spinal cord injury.

Spinal cord injury (SCI) results in a dramatic loss of bone mineral and a marked increase in fracture incidence in the femur; however, its effect on the femur's geometric structure and strength is poorly studied. The primary purpose of the present study was to assess the geometric structure, composition, and strength of the midfemur in men with long-term (>2 years), complete SCI (C6-L1 level; n=7) relative to men without SCI (n=8). T1-weighted axial images of the thigh were collected on a GE 1.5-T magnetic resonance imager and geometric, structure, composition, and strength measurements of the midfemur and skeletal muscle volume of the midthigh were determined. Areal bone mineral density (aBMD), bone mineral content (BMC), and bone area of the midthird of the femur and arms were determined using dual-energy X-ray absorptiometry. There were no differences in age, height, weight, femur length, arm BMC, arm aBMD, or arm bone area between the SCI group and controls. While the volume of the midfemur was not different in the two groups, the medullary cavity had 53% more volume and was 21-25% wider in the SCI group (P<0.05). In contrast, the cortical wall in the SCI group had a 24% lower volume and was 27-47% thinner (P<0.05). The cortical wall was particularly thin in the posterior section of the bone. The SCI group also had lower BMC and aBMD in the midfemur (21% and 25%, respectively, P<0.05). Calculated cross-sectional moment of inertia (CSMI), section modulus (Z), and polar moment of inertia (J) were lower in the SCI group (13-19%, P<0.05). A higher ratio of cortical bone volume to muscle volume and BMC to muscle volume in the SCI group (P<0.05) suggests that there was a greater loss of muscle than cortical bone after SCI; however, muscle volume was strongly correlated with cortical bone volume and BMC in the SCI and control groups (r=0.71 to 0.90, P<0.05). Muscle volume was also moderately to strongly correlated with CSMI and Z in the anterior-posterior direction and J. Muscle volume was weakly correlated or not correlated with bone strength measures in the control group (P>0.05). These findings suggest that after SCI, the midfemur erodes on the endosteal surface, resulting in a decreased resistance to bending and torsion. Although midthigh muscle volume appears to decline to a greater degree than midfemur cortical bone volume and BMC, their relationships remain strong.

Effect of physical activity on MRI-measured blood oxygen level-dependent transients in skeletal muscle after brief contractions.

The signal intensity (SI) in gradient-echo, echo-planar magnetic resonance images (repetition time/echo time = 1,000/40) of anterior tibialis muscle in active [estimated energy expenditure 42.4 +/- 3.7 (SD), n = 8] vs. sedentary (32.3 +/- 0.6 kcal.kg(-1).day(-1), n = 8) young adult (18-34 yr old) human subjects was measured after single, 1-s-duration maximum voluntary ankle dorsiflexion contractions. There was no difference between groups in anterior tibial muscle cross-sectional area or peak force. In both groups there was a transient increase in anterior tibialis muscle SI, which peaked 5-7 s after the end of each contraction. The magnitude of the SI transient was over threefold greater [5.5 +/- 1.0 (SE) vs. 1.5 +/- 0.4%] and persisted twice as long (half-recovery time 5.4 +/- 0.4 vs. 2.7 +/- 0.3 s) in the active subjects. In the same subjects, blood flow in popliteal, anterior tibial, and posterior tibial arteries was measured by cardiac-gated CINE magnetic resonance angiography before and after 2 min of dynamic, repetitive ankle dorsiflexion exercise. There was no difference between groups in resting or postexercise flow in anterior tibial artery, although popliteal and posterior tibial artery flow after exercise tended to be greater in the active group. The results indicate that transient hyperemia and oxygenation in muscle after single contractions are enhanced by chronic physical activity to a greater extent than peak muscle blood flow.