Effect of Knee Position on Muscle Loss During Leg Immobilization

Official title

A Novel Angle: Manipulating Knee Position to Understand Muscle Deterioration During Leg Immobilization

Overview

This study looks at what happens to leg muscles when the knee is kept straight or bent during five days of wearing a brace. We want to find out if keeping the knee bent (so the thigh muscle is stretched) helps prevent muscle loss compared to keeping the knee straight. Thirty healthy adults will take part. They will wear a knee brace for five days and have several tests before and after, including scans, blood samples, and small muscle samples. The results may help doctors find better ways to protect muscles when people cannot move, for example after surgery or illness.

Detailed description

Short periods of physical inactivity, as occur during illness, surgery, or injury, lead to rapid and substantial losses of muscle mass, strength, and metabolic health, often with incomplete recovery in vulnerable individuals. In older adults, repeated bouts of disuse are thought to contribute significantly to age-related sarcopenia. Despite decades of research, the underlying mechanisms remain incompletely elucidated, and effective therapeutic interventions are lacking.

Mechanistically, any muscle atrophy must occur due to a negative muscle protein net balance (MPNB), which can be caused by a decline in muscle protein synthesis (MPS), an increase in muscle protein breakdown (MPB), or a combination of both. Normally, exercise and dietary protein stimulate MPS and maintain muscle mass. During disuse, however, exercise is often impossible, and inactive muscle shows a blunted response to dietary protein. Consequently, these potent strategies become ineffective or even harmful in inactive individuals, highlighting the need for alternative approaches.

Animal studies indicate that immobilizing a muscle in a lengthened (stretched) position can attenuate disuse-induced muscle atrophy and functional decline compared to a shortened position. Whether this phenomenon also occurs in humans, and whether passive muscle length and tension influence muscle metabolism during disuse, remain unexplored.

The objective of this study is to assess whether immobilizing the quadriceps in a lengthened versus neutral position during disuse attenuates losses of muscle mass, function, and metabolic health.

In this randomized, controlled human intervention study with 2 parallel groups 30 healthy, normal weight males and females (18-40 years old, BMI between 18 and 30 kg·m-2) will undergo 5 days of unilateral leg immobilization using a knee brace that prevents voluntary quadriceps contraction. In the neutral group, the leg is fixed in full extension (0° flexion), while in the lengthened group it is fixed at 60° flexion, stretching the quadriceps.

The effects on muscle protein net balance (MPNB), quadriceps muscle volume , muscle quality, muscle strength, fatigue resistance, and muscle mitochondrial bioenergetics will be assessed.

Interventions

• Device Knee immobilization brace (0°) for 5 days
  Unilateral knee immobilization at 0° flexion for 5 days using a brace; post-immobilization metabolic testing with tracer infusions and biopsies
• Device Knee immobilization brace (60°) for 5 days
  Unilateral knee immobilization at 60° flexion for 5 days using a brace; post-immobilization metabolic testing with tracer infusions and biopsies

Primary outcome measures

• Muscle protein net balance (MPNB) [Time frame: Baseline to 3 hours after tracer infusion]

Secondary outcome measures (10)

• Thigh muscle volume [Time frame: Baseline and after 5 days of immobilization]
• Muscle strength [Time frame: Baseline and after 5 days of immobilization]
• Muscle fatigue [Time frame: Baseline and after 5 days of immobilization]
• Intramuscular fat content [Time frame: Baseline and after 5 days of immobilization]
• Muscle metabolite concentrations [Time frame: Baseline and after 5 days of immobilization]
• Mitochondrial respiration [Time frame: Baseline and after 5 days of immobilization]
• Mitochondrial reactive oxygen species production [Time frame: Baseline and after 5 days of immobilization]
• Mitochondrial calcium retention capacity [Time frame: Baseline and after 5 days of immobilization]
• Muscle gene expression related to atrophy [Time frame: Baseline and after 5 days of immobilization]
• Muscle protein markers of atrophy [Time frame: Baseline and after 5 days of immobilization]

Eligibility criteria

Inclusion criteria

• Healthy males and females
• Aged from 18-40 years at the time of signing informed consent
• 18.5 < BMI < 30 kg·m-2
• Must be willing and able to communicate and participate in the whole study

Exclusion criteria

• Smoking
• Diabetes (Type 1, Type 2, or genetic form of diabetes)
• Any diagnosed cardiovascular (heart) disease or high blood pressure (≥140 mmHg systolic and/or ≥90 mmHg diastolic)
• Chronic use of any prescribed or over the counter pharmaceuticals that may modulate muscle protein metabolism (excluding oral contraceptives and contraceptive devices).
• A personal or family history of thrombosis, epilepsy, seizures or schizophrenia.
• Prone to keloid forming (i.e. hyperplastic growth of scars).
• Any known disorders in muscle metabolism
• Regular use of dietary protein and/or amino acid supplements (>3 times per week)
• Currently involved in a structured progressive resistance training programme (>3 times per week)
• Known allergy to lidocaine
• Known severe kidney problems
• Allergy to one or multiple amino acids
• Recent (within the last 6 months) or current musculoskeletal injury (e.g. leg fracture)
• Having received or ingested a stable isotope tracer containing 15N in the past
• Contra-indications for MRI such as incompatible metal objects in the body and claustrophobia.
• Currently taking part in other scientific research
• Pregnant or breastfeeding
• Unable to give consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• World Medical Association Inc. Declaration of Helsinki. Ethical principles for medical research involving human subjects. J Indian Med Assoc. 2009 Jun;107(6):403-5. No abstract available. PMID 19886379
• Wolfe, R.R.C., D.L., Isotope Tracers in Metabolic Research: Principles and Practice of Kinetic Analysis. 2004.
• Gouspillou G, Sgarioto N, Kapchinsky S, Purves-Smith F, Norris B, Pion CH, Barbat-Artigas S, Lemieux F, Taivassalo T, Morais JA, Aubertin-Leheudre M, Hepple RT. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 2014 Apr;28(4):1621-33. doi: 10.1096/fj.13-242750. Epub 2013 Dec PMID 24371120
• Holloway GP, Holwerda AM, Miotto PM, Dirks ML, Verdijk LB, van Loon LJC. Age-Associated Impairments in Mitochondrial ADP Sensitivity Contribute to Redox Stress in Senescent Human Skeletal Muscle. Cell Rep. 2018 Mar 13;22(11):2837-2848. doi: 10.1016/j.celrep.2018.02.069. PMID 29539414
• Pinckaers PJ, Petrick HL, Horstman AM, Moreno-Asso A, De Marchi U, Hendriks FK, Kuin LM, Fuchs CJ, Grathwohl D, Verdijk LB, Zorenc AH, Senden JM, Migliavacca E, Metairon S, Poquet L, Morin-Rivron D, Karagounis LG, Holloway GP, Feige JN, van Loon LJ. Oleuropein Supplementation Increases Resting Skeletal Muscle Fractional Pyruvate Dehydrogenase Activity but Does Not Influence Whole-Body Metabolism: PMID 39993475
• Pavis GF, Abdelrahman DR, Murton AJ, Wall BT, Stephens FB, Dirks ML. Nasogastric bolus administration of a protein-rich drink augments insulinaemia and aminoacidaemia but not whole-body protein turnover or muscle protein synthesis versus oral administration. Clin Sci (Lond). 2024 Jan 10;138(1):43-60. doi: 10.1042/CS20231126. PMID 38112515
• Dirks ML, Wall BT, Kramer IF, Zorenc AH, Goessens JP, Gijsen AP, van Loon LJ. A single session of neuromuscular electrical stimulation does not augment postprandial muscle protein accretion. Am J Physiol Endocrinol Metab. 2016 Jul 1;311(1):E278-85. doi: 10.1152/ajpendo.00085.2016. Epub 2016 Jun 7. PMID 27279248
• West S, Monteyne AJ, Whelehan G, Abdelrahman DR, Murton AJ, Finnigan TJA, Blackwell JR, Stephens FB, Wall BT. Mycoprotein ingestion within or without its wholefood matrix results in equivalent stimulation of myofibrillar protein synthesis rates in resting and exercised muscle of young men. Br J Nutr. 2023 Jul 14;130(1):20-32. doi: 10.1017/S0007114522003087. Epub 2022 Sep 29. PMID 36172885

Identifiers

NCT: NCT07690150 · NL010759

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗