Cellular Mechanisms Involved in Muscle Pathology

NCT05798962 | Recruiting DMC

• 1 other identifier: P162
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The overall purpose of this proposed study is the understanding of cellular mechanisms involved in the pathologic fatty degeneration of muscle. Fatty infiltration in skeletal muscle is observed following sports injuries such as muscle strain injuries and Achilles tendon rupture. It is also observed in the degenerative state after rotator cuff tears as well as in the aging process. While fatty degeneration of skeletal muscle occurs in many different conditions and is known to decrease muscle function, the cellular processes involved in fatty infiltration have not been investigated in human muscle. Hypotheses:

1. 1.There is a high amount of fibro-adipogenic progenitors (FAPs) with an adipogenic pattern in pathologic skeletal muscle following a muscle strain injury and a full Achilles tendon rupture. We hypothesize that there is an increased number of FAPs with an adipogenic signature already in the acute phase after a strain injury, but a significantly higher number in the chronic stage as well as in the muscle following an Achilles tendon rupture.
2. 2.Mechanical cues are a major driver of the phenotypic drift of FAPs. The lack of mechanical stimuli initiates the adoption of an adipogenic pathway in naïve FAPs, whereas naïve FAPs exposed to mechanical stimuli will maintain their undifferentiated phenotype.
3. 3.The adherence of FAPs to a soft material will activate the adoption of an adipogenic phenotype, whereas a stiff material will favor a more fibrotic phenotype in naïve FAP's isolated from healthy skeletal muscle.

Conditions

Muscle Strain, Lower Leg; Muscle Strained Thigh; Achilles Tendon; Laceration; Fatty Degeneration

Outcome Measures

Primary Outcomes (1)

• Presence and number of Fibro-adipogenic progenitors

  Determination of the number and the phenotypic appearance of fibro-adipogenic progenitors in the injured compared to the healthy muscle

  2 years: Sampling and analyses

Secondary Outcomes (2)

• Cell cluster analysis

  2 years: Sampling and analyses

• Importance of mechanical stimuli for Fibro-adipogenic progenitors

  2 years: Sampling and analyses

Study Arms (3)

Acute muscle strain

Subjects with an acute muscle strain (within 14 days post injury) in either the hamstrings or the calf muscles

Procedure: Biopsies

Chronic muscle strain

Subjects with a chronic muscle strain more than 6 months prior to inclusion in either the hamstrings or the calf muscles

Procedure: Biopsies

Achilles tendon rupture

Subjects with a full Achilles tendon rupture more than 12 months prior to inclusion

Procedure: Biopsies

Interventions

Biopsies PROCEDURE

Biopsies from the pathological muscle and healthy, unaffected muscle

Achilles tendon rupture; Acute muscle strain; Chronic muscle strain

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Healthy individuals with an acute or previous muscle strain injury or a previous Achilles tendon rupture

You may qualify if:

• years and older, male and female, with an acute muscle strain injury (\<14 days post injury) in the calf or hamstring muscles (group 1). Pathological changes visible on an ultrasound scan as hypoechoic areas.

You may not qualify if:

• Type I and II Diabetes, Connective tissue and/or rheumatic diseases, or any observed organ dysfunctions
• Daily smoking
• Persons with daily intake of non-steroidal anti-inflammatory drugs (NSAIDs) within three months prior to time of contact
• Allergic reactions to local anesthesia
• Use of anticoagulant treatment
• Needle phobia
• Any drug or alcohol abuse now or in the past
• The absence of any pathological changes visible on an ultrasound scan as hypo-/ hyperechoic areas (group 1 and 2)
• The absence of any pathological changes (fatty degeneration) in either the gastrocnemius or the soleus muscle visible on an ultrasound scan (Subject group 3)

Sponsors & Collaborators

• Bispebjerg Hospital: lead

Study Sites (1)

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Nielsine Nielsen Vej 11, Building 8

Copenhagen, 2400, Denmark

RECRUITING

Related Publications (6)

• Bayer ML, Hoegberget-Kalisz M, Jensen MH, Olesen JL, Svensson RB, Couppe C, Boesen M, Nybing JD, Kurt EY, Magnusson SP, Kjaer M. Role of tissue perfusion, muscle strength recovery, and pain in rehabilitation after acute muscle strain injury: A randomized controlled trial comparing early and delayed rehabilitation. Scand J Med Sci Sports. 2018 Dec;28(12):2579-2591. doi: 10.1111/sms.13269. Epub 2018 Aug 16.

  PMID: 30043997 BACKGROUND

• Ekstrand J, Walden M, Hagglund M. Hamstring injuries have increased by 4% annually in men's professional football, since 2001: a 13-year longitudinal analysis of the UEFA Elite Club injury study. Br J Sports Med. 2016 Jun;50(12):731-7. doi: 10.1136/bjsports-2015-095359. Epub 2016 Jan 8.

  PMID: 26746908 BACKGROUND

• Bayer ML, Hoegberget-Kalisz M, Svensson RB, Hjortshoej MH, Olesen JL, Nybing JD, Boesen M, Magnusson SP, Kjaer M. Chronic Sequelae After Muscle Strain Injuries: Influence of Heavy Resistance Training on Functional and Structural Characteristics in a Randomized Controlled Trial. Am J Sports Med. 2021 Aug;49(10):2783-2794. doi: 10.1177/03635465211026623. Epub 2021 Jul 15.

  PMID: 34264782 BACKGROUND

• Gladstone JN, Bishop JY, Lo IK, Flatow EL. Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome. Am J Sports Med. 2007 May;35(5):719-28. doi: 10.1177/0363546506297539. Epub 2007 Mar 2.

  PMID: 17337727 BACKGROUND

• Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010 Feb;12(2):143-52. doi: 10.1038/ncb2014. Epub 2010 Jan 17.

  PMID: 20081842 BACKGROUND

• Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M, Yamaguchi M, Ogawa R, Matev MM, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Tsuchida K, Yamamoto H, Fukada S. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci. 2011 Nov 1;124(Pt 21):3654-64. doi: 10.1242/jcs.086629. Epub 2011 Nov 1.

  PMID: 22045730 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

1 biopsy from the pathological skeletal muscle 1 biopsy from the contralateral, healthy muscle (i.e. the healthy muscle corresponding to the injured muscle) 1 biopsy from the healthy, uninjured vastus lateralis muscle

MeSH Terms

Conditions

Sprains and Strains; Lacerations; Fatty Liver

Interventions

Biopsy

Condition Hierarchy (Ancestors)

Wounds and Injuries; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Monika L Bayer, PhD

  Bispebjerg Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Monika L Bayer, PhD

CONTACT

004525687931; Monika.lucia.bayer@regionh.dk

Michael Kjaer, DMSci

CONTACT

004538636022; michaelkjaer@sund.ku.dk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Researcher

Study Record Dates

• First Submitted: February 27, 2023
• First Posted: April 5, 2023
• Study Start: April 5, 2023
• Primary Completion: February 28, 2025
• Study Completion (Estimated): August 31, 2030
• Last Updated: April 6, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)