Lean regional muscle volume estimates using explanatory bioelectrical models in healthy subjects and patients with muscle wasting

AbstractThis study aimed to validate a fully automatic method to quantify knee-extensor muscle volume and exercise-induced hypertrophy. By using a magnetic resonance imaging-based fat-water separated two-point Dixon sequence, the agreement between automated and manual segmentation of a specific ~15-cm region (partial volume) of the quadriceps muscle was assessed. We then explored the sensitivity of the automated technique to detect changes in both complete and partial quadriceps volume in response to 8 weeks of resistance training in 26 healthy men and women. There was a very strong correlation (r = 0.98, P < 0.0001) between the manual and automated method for assessing partial quadriceps volume, yet the volume was 9.6% greater with automated compared with manual analysis (P < 0.0001, 95% limits of agreement −93.3 ± 137.8 cm3). Partial muscle volume showed a 6.0 ± 5.0% (manual) and 4.8 ± 8.3% (automated) increase with training (P < 0.0001). Similarly, the complete quadriceps increased 5.1 ± 5.5% with training (P < 0.0001). The intramuscular fat proportion decreased (P < 0.001) from 4.1% to 3.9% after training. In conclusion, the automated method showed excellent correlation with manual segmentation and could detect clinically relevant magnitudes of exercise-induced muscle hypertrophy. This method could have broad application to accurately measure muscle mass in sports or to monitor clinical conditions associated with muscle wasting and fat infiltration.

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Automatic and quantitative assessment of regional muscle volume by multi-atlas segmentation using whole-body water-fat MRI

Journal of Magnetic Resonance Imaging ◽

10.1002/jmri.24726 ◽

2014 ◽

Vol 41 (6) ◽

pp. 1558-1569 ◽

Cited By ~ 83

Author(s):

Anette Karlsson ◽

Johannes Rosander ◽

Thobias Romu ◽

Joakim Tallberg ◽

Anders Grönqvist ◽

...

Keyword(s):

Quantitative Assessment ◽

Body Water ◽

Muscle Volume ◽

Whole Body ◽

Atlas Segmentation ◽

Regional Muscle

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Safety of the antimyostatin monoclonal antibody LY2495655 in healthy subjects and patients with advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2516 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2516-2516 ◽

Cited By ~ 10

Author(s):

Gayle S. Jameson ◽

Daniel D. Von Hoff ◽

Glen J. Weiss ◽

Donald A. Richards ◽

David A. Smith ◽

...

Keyword(s):

Monoclonal Antibody ◽

Phase I ◽

Healthy Volunteers ◽

Cancer Patients ◽

Advanced Cancer ◽

Dose Escalation ◽

Healthy Subjects ◽

Small Sample ◽

Muscle Volume ◽

Thigh Muscle

2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.

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Computed tomography-derived assessments of regional muscle volume: Validating their use as predictors of whole body muscle volume in cancer patients

British Journal of Radiology ◽

10.1259/bjr.20180451 ◽

2018 ◽

Vol 91 (1092) ◽

pp. 20180451 ◽

Cited By ~ 2

Author(s):

Darragh F Halpenny ◽

Marcus Goncalves ◽

Emily Schwitzer ◽

Jennifer Golia Pernicka ◽

Jasmyne Jackson ◽

...

Keyword(s):

Computed Tomography ◽

Cancer Patients ◽

Muscle Volume ◽

Whole Body ◽

Body Muscle ◽

Regional Muscle

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Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

International Journal of Molecular Sciences ◽

10.3390/ijms21031092 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1092 ◽

Cited By ~ 1

Author(s):

Nissrine Daou ◽

Medhi Hassani ◽

Emidio Matos ◽

Gabriela Salim De Castro ◽

Raquel Galvao Figueredo Costa ◽

...

Keyword(s):

Cancer Patients ◽

Healthy Subjects ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Muscle Fibers ◽

Progressive Increase ◽

Tumor Bearing ◽

Central Nuclei ◽

Bona Fide ◽

Motor Neuron Loss

An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.

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Reflex Responses in Upper Limb Muscles to Cutaneous Stimuli

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100048174 ◽

1993 ◽

Vol 20 (04) ◽

pp. 271-278 ◽

Cited By ~ 30

Author(s):

R. Chen

Keyword(s):

Stimulus Intensity ◽

Upper Limb ◽

Healthy Subjects ◽

Voluntary Contraction ◽

Cutaneous Reflexes ◽

Focal Lesions ◽

Normal Ranges ◽

Conduction Velocities ◽

Limb Muscles ◽

Biphasic Responses

ABSTRACT:Cutaneous reflexes in the upper limb were elicited by stimulating digital nerves and recorded by averaging rectified EMG from proximal and distal upper limb muscles during voluntary contraction. Distal muscles often showed a triphasic response: an inhibition with onset about 50 ms (Il) followed by a facilitation with onset about 60 ms (E2) followed by another inhibition with onset about 80 ms (12). Proximal muscles generally showed biphasic responses beginning with facilitation or inhibition with onset at about 40 ms. Normal ranges for the amplitude of these components were established from recordings on 22 arms of 11 healthy subjects. An attempt was made to determine the alterent fibers responsible for the various components by varying the stimulus intensity, by causing ischemic block of larger fibers and by estimating the afferent conduction velocities. The central pathways mediating these reflexes were examined by estimating central delays and by studying patients with focal lesions

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The ubiquitin–proteasome system and skeletal muscle wasting

Essays in Biochemistry ◽

10.1042/bse0410173 ◽

2005 ◽

Vol 41 ◽

pp. 173-186 ◽

Cited By ~ 110

Author(s):

Didier Attaix ◽

Sophie Ventadour ◽

Audrey Codran ◽

Daniel Béchet ◽

Daniel Taillandier ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Wasting ◽

Proteolytic Enzymes ◽

Cathepsin L ◽

Ubiquitin Proteasome System ◽

Complete Breakdown ◽

Skeletal Muscle Proteins ◽

Ubiquitin Proteasome ◽

Tripeptidyl Peptidase Ii ◽

F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

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