Role of HIF-1α in Skeletal Muscle Aging

NCT ID: NCT03371134

Last Updated: 2017-12-14

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 16 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-01-10
• Study Completion Date: 2020-07-26

Brief Summary

Deficits in skeletal muscle function exist during aging and muscular dystrophy, and suboptimal function has been related to factors such as atrophy, excessive inflammation and fibrosis. Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. This interest stems from the fact that sarcopenia is both common and associated with serious health consequences in terms of frailty, disability, morbidity and mortality. The age-related loss of human skeletal muscle mass is due to a decrease in myofibre size and number with the loss of both fast and slow type myofibres, although the loss of fast myofibres tends to start earlier, at ∼70 years. Many factors influence the decrease in muscle mass. A significant contributor is an anabolic resistance of older skeletal muscle to protein nutrition as seen during immobilisation which can be ameliorated at least in part by resistance exercise and dietary supplementation. Other intensive areas of research are related to the loss of innervation and oxidative damage. Moreover, ineffective muscle regeneration underlies each condition and has been attributed to a deficit in myogenic potential of resident stem cells or satellite cells. It is now widely accepted that satellite cells, and generally adult stem cells, are normally quiescent and tend to reside in hypoxic areas of the tissue to preserve their undifferentiated state. To govern these processes, cells have developed a very complex machinery that is mainly regulated by a group of transcription factors known as hypoxia-inducible factors (HIFs). In particular, several observations support the idea that oxygen deprivation and HIF-1a may play a key role during ischemia to activate the regeneration process, which, after an initial hypoxic insult, needs to proceed under normoxia. On these bases, in this study we will investigate the role of HIF-1a in skeletal atrophy during aging.

Detailed Description

Deficits in skeletal muscle function exist during aging and muscular dystrophy, and suboptimal function has been related to factors such as atrophy, excessive inflammation and fibrosis. Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. This interest stems from the fact that sarcopenia is both common and associated with serious health consequences in terms of frailty, disability, morbidity and mortality. The age-related loss of human skeletal muscle mass is due to a decrease in myofibre size and number with the loss of both fast and slow type myofibres, although the loss of fast myofibres tends to start earlier, at ∼70 years. Many factors influence the decrease in muscle mass. A significant contributor is an anabolic resistance of older skeletal muscle to protein nutrition as seen during immobilisation which can be ameliorated at least in part by resistance exercise and dietary supplementation. Other intensive areas of research are related to the loss of innervation and oxidative damage. Moreover, ineffective muscle regeneration underlies each condition and has been attributed to a deficit in myogenic potential of resident stem cells or satellite cells. It is now widely accepted that satellite cells, and generally adult stem cells, are normally quiescent and tend to reside in hypoxic areas of the tissue to preserve their undifferentiated state. To govern these processes, cells have developed a very complex machinery that is mainly regulated by a group of transcription factors known as hypoxia-inducible factors (HIFs). In particular, several observations support the idea that oxygen deprivation and HIF-1a may play a key role during ischemia to activate the regeneration process, which, after an initial hypoxic insult, needs to proceed under normoxia. On these bases, in this study we will investigate the role of HIF-1a in skeletal atrophy during aging.

In particular, we will isolate satellite cells from muscular biopsies harvested from old sarcopenic patients and from young patients. The, we will measure HIF-1a levels and we will compare them.

Conditions

Sarcopenia

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Sarcopenic group

Harvesting of muscular biopsies Muscular biopsies will be harvested from old sarcopenic patients undergoing hip replacement surgery

Harvesting of muscular biopsies

Intervention Type: BIOLOGICAL

Muscular biopsies will be harvested during surgery; them satellite cells will be isolated and characterized in vitro.

Control group

Harvesting of muscular biopsies Muscular biopsies will be harvested from young patients undergoing Anterior Cruciate Ligament (ACL) reconstruction surgery

Harvesting of muscular biopsies

Intervention Type: BIOLOGICAL

Muscular biopsies will be harvested during surgery; them satellite cells will be isolated and characterized in vitro.

Interventions

Harvesting of muscular biopsies

Muscular biopsies will be harvested during surgery; them satellite cells will be isolated and characterized in vitro.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Sarcopenic patients (measured by DXA) affected by hip osteoarthritis, developmental dysplasia of the hip or hip fracture and undergoing hip replacement surgery (for the sarcopenic group)
• Patients affected by traumatic ACL tears and undergoing ACL reconstruction surgery (for the control group)
• Patients between 18 and 35 years old (for the control group)
• Patients between 65 and 90 years old (for the sarcopenic group)
• 18 ≤ Body Mass Index (BMI) ≤ 30 kg/m2

Exclusion Criteria

• Diseases that can affect bone or muscle metabolism
• Pharmacological therapies that can interact with bone or muscle metabolism
• Bone metastases
• Bone infections
• HIV, hepatitis B virus, hepatitis C virus or Treponema pallidum positivity
• BMI ≥30kg/m2

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

I.R.C.C.S Ospedale Galeazzi-Sant'Ambrogio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Laura Mangiavini, Dr

Role: PRINCIPAL_INVESTIGATOR

IRCCS Istituto Ortopedico Galeazzi

Central Contacts

Laura Mangiavini, Dr

Role: CONTACT

Phone: 00390266214930

Email: laura.mangiavini@grupposandonato.it

Other Identifiers

HIF

Identifier Type: -

Identifier Source: org_study_id