Sarcopenia and mitochondrial dysfunction in people living with HIV: the impact of ageing

1 December 2023. Related: Conference reports, Ageing and life expectancy, HIV and Ageing 2023.

Kirk Taylor, HIV i-Base

The 2023 14th International Workshop on HIV and Ageing included many excellent plenary talks and discussions.

This included the opening session on sarcopenia, with oral presentations on age-related changes of muscle physiology, hallmarks of ageing and mitochondrial dysfunction, and defining sarcopenia. [1, 2, 3]

HIV is associated with more rapid declines in mitochondrial function but can be improved with exercise. [2]

Mitochondrial copy number can be used to identify ART-associated mitochondrial dysfunction.

Although there is no current consensus on the definition of sarcopenia, different research groups generally agree that this should include weakness (low grip strength for men <35.5 kg and women <20 kg) and slowness (low walking speed <0.8 m/s). [3]

Muscle structure and changes with ageing

Dr Gustavo Duque of McGill University Health Centre gave an overview of sarcopenia and changes in muscle tone and physiology that occur with ageing. [1]

Skeletal muscle is a complex tissue that directly interacts with the bone to facilitate movement. At its core, muscle is a collection of myofibrils that respond to myofilament contraction and relaxation in an ATP-dependent manner. These myofibrils are organised into muscle fibres, which form larger bundles that respond in a coordinated manner to nervous innervation.

Muscle accounts for up to 40% of body mass and regulates movement and metabolism. However, different muscle fibre types have specific properties and are adapted to either slow (type I) or fast (type II) responses.

Several muscle properties also directly influence health and disease.

Neuromuscular junctions coordinate desired movement.
Blood vessels deliver nutrients of oxygen and collect and distribute messenger molecules (myokines).
Resident FAP (fibrotic/adipogenic progenitor) and stem cells coordinate responses and remodel following injury and environmental cues.

Hallmarks of ageing are driven by epigenetics, stem cell changes, mitochondrial dysregulation and metabolic changes. These factors determine the rate of muscular ageing and are the focus of current research.

Crucially, as part of the ageing process, fast fibres are steadily replaced by slow fibres, fat levels increase, and neuromuscular junctions begin to uncouple. The term inflammageing is used to refer to the chronic accumulation of inflammatory mediators that negatively impact muscle homeostasis and drive the accumulation of intramuscular fat in most people.

The large Australian Body Study in the general population used DEXA scans to show age-related muscle loss in people aged 18 to 88 (n=15,479). Muscle mass declined with similar trends for male and female participants with atrophy of 0.5% to 1% per year.

Sarcopenia is associated with ageing but can be triggered by a range of factors including obesity, inflammation, low levels of physical activity and chronic health conditions including HIV. Sarcopenic muscles have very few fibres and a high fat content.

This means that bone health and muscle health are critically interdependent. Osteoporosis and sarcopenia have common risk factors and the increased risk of falls after muscle loss increases the risk of fractures which is also linked to age-related reductions in bone mineral density.

The AMBERS study of post-menopausal women aged 75 to 80 years (n=312) reported a link between fat levels in the bone marrow and muscle, with increased osteosarcopenia risk. The two major risk factors were ageing and poor nutrition.

Mitochondrial (dys)function and ageing

Dr Jing Sun of John’s Hopkins University discussed mitochondria (dys)function and its links with sarcopenia for people living with HIV. [2]

Inflammageing in people living with HIV is a complex process driven by both viral factors (related to ART use and reservoir size) and lifestyle factors (including diet and exercise). This leads to mitochondrial damage, epigenetic changes, stem cell exhaustion and immunosenescence.

Mitochondria (mT) synthesis of ATP is essential for muscular contraction.

Mitochondrial DNA (mtDNA) haplogroups can be used to assess ageing characteristics for different geographical populations. For example, European men living with HIV (aged ≥50 years, n=455) within haplogroup J have a more rapid decline of walking speed as they get older. Meanwhile, Black women living with HIV haplogroup L2 were associated with lower incidence of diabetes compared to those in haplogroup L3 who had increased risk.

Analysis of mtDNA and copy number from the UK Biobank has also been performed to assess disease risk related to inherited or environmental factors.

Accrual of environmental-associated mtDNA mutations increases the risk of negative health outcomes and is associated with mortality risk. For example, significant associations were reported between environmental mtDNA mutations and all-cause mortality (HR 1.28; 95% CI: 1.20 to 1.37), digestive disorders (HR 1.47; 95% CI: 1.05 to 2.05) and neoplasms (HR 1.37; 95% CI: 1.25 to 1.50).

This talk explained that mT copy number is a surrogate marker of the quantity and function of mT and was used to highlight mT dysfunction with early generation NRTIs.

In the ALIVE cohort of people who injected drugs, mT copy number was derived from peripheral blood samples. Participants were living with HIV (n=543, 59%) and median age was 48 years. Copy number was lower for people living with HIV although significant declines were not observed for people who were taking ART, had CD4 counts >500 cells/mm³ or had undetectable viral load. Participants that had <200 CD4 cells/mm³, detectable viraemia, or were not taking their ART had the greatest decline of mT copy number.

Mitochondrial copy number also declines more rapidly during ageing for people living with HIV than for HIV negative individuals. The lowest quartile of copy number is associated with the greatest mortality risk and people within this group are more susceptible to kidney disease and kidney function decline.

Ongoing studies are evaluating the potential to improve mT function through increased exercise. Mitochondrial function was evaluated before and after six months of exercise. Participants were aged between 50 to 75 years and 12/30 participants were living with HIV. Exercise improved mT function, but the magnitude of change was smaller for people living with HIV.

The HEALTH study is currently enrolling people living with HIV to evaluate the best type of exercise to improve mT function and promote healthy ageing. The impact of continuous moderate exercise will be compared to high intensity interval training (HIIT).

Standardising sarcopenia definitions

Dr Peggy Cawthon of the California Pacific Medical Centre Research Institute discussed methods for monitoring sarcopenia and standardisation of sarcopenia definitions. [3]

Although DEXA scans are widely used to measure lean muscle mass, this approach is subject to measurement error and there is no gold standard alternative.

There are also differences between different sarcopenia consensus statements, although all agree that it is a multicomponent syndrome defined by muscle size and other factors. However, each statement has different thresholds and uses different measures for each component.

The European working group has three components: (1) low muscle strength, (2) low muscle quantity or quality and (3) low physical performance.

Depending on the consensus method used, sarcopenia prevalence in the elderly ranges from 10% to 40%.

Although sarcopenia definitions predict outcomes, it is unclear which components are most informative. The Sarcopenia Outcomes and Definitions Consortium (SDOC) are now reviewing and refining definitions and highlighting controversies within this field.

This group evaluated grip strength, lean mass and walking speed to produce the following summary:

“Low grip strength and low usual walking speed independently predict adverse health-related outcomes such as mobility limitation, falls, disability and mortality in community-dwelling older adults”.

Both weakness (low grip strength for men <35.5 kg and women <20kg) and slowness (low walking speed <0.8 m/s) are easy to measure and should be included in the definition of sarcopenia.

In contrast, DEXA measures have a high degree of uncertainty and should not be used, either to predict sarcopenia risk or in the definition of sarcopenia.

The session concluded with a lively audience discussion.

Dr Duque commented that it is difficult to disaggregate biological and environmental factors that contribute to muscular ageing. Genetic factors also influence the ageing process. Some DEXA data shows that age-related muscle decline occurs irrespective of demographics.

Exercise improves muscle tone, and it is likely that HIIT will prove more beneficial than continuous moderate exercise. However, there is a decreased ability to respond to the same input over time. LIFE study data show that age-related complicating factors reduce adherence to exercise regimes (e.g. falls, fractures and illness).

Dr Duque discussed fat infiltration into muscles and that some sites are preferentially targeted (e.g. quadriceps). Infiltration of fat influences muscle structure and tone and could therefore be a measure of sarcopenia. Ongoing work is using advanced computer learning to evaluate fat infiltration from DEXA data.

Biopsies of muscle with fat infiltrates from people living with HIV look similar to older people with sarcopenia, but it is unclear whether it is caused by the same mechanisms or due, for example, to lipodystrophy as a side effect of ART. Observational data from the WIHS cohort show increased fat infiltration into muscle and impaired physical function for people living with HIV.

Luckily, osteoporosis drugs can improve muscle mass and function and reducing osteoporosis in studies lead to fewer falls, suggesting clinical benefits from improved muscle mass and function.

Links between mitochondrial copy number and ART classes were also discussed.

Self-reported data did not show a sizeable effect based on length of exposure to drugs, but there was a limited effect of drug class on copy number. Some studies report changes of mitochondrial copy number with ART use, but some studies do not normalise copy number relative to cell counts (e.g. platelets and leukocytes).

Dr Cawthon also discussed ways of measuring muscle mass that is included in a separate report in this issue of HTB. [4]

References

Unless stated otherwise, all references are to the 14th International Workshop on HIV and Ageing, 26 to 27 October 2023, Washington, USA.
https://academicmedicaleducation.com/meeting/international-workshop-hiv-aging-2023

Duque G. General/functional lecture on sarcopenia, changes in muscle with aging. 14th International Workshop on HIV and Ageing, 26 to 27 October 2023, Washington, USA. Oral presentation; Session 1: Sarcopenia.
Sun J. Mitochondrial function and aging. 14th International Workshop on HIV and Ageing, 26 to 27 October 2023, Washington, USA. Oral presentation; Session 1: Sarcopenia.
Cawthon P. How to measure sarcopenia. 14th International Workshop on HIV and Ageing, 26 to 27 October 2023, Washington, USA. Oral presentation; Session 1: Sarcopenia.
Taylor K. Measuring sarcopenia in people living with HIV. HTB (1 December 2023).
https://i-base.info/htb/46706