Age-Related Changes in Skeletal Muscle Iron Homeostasis

Abstract

Sarcopenia is an age-related condition of slow, progressive loss of muscle mass and strength, which contributes to frailty, increased risk of hospitalisation and mortality, and increased health care costs. The incidence of sarcopenia is predicted to increase to >200 million affected older adults worldwide over the next 40 years, highlighting the urgency for understanding biological mechanisms and developing effective interventions. An understanding of the mechanisms underlying sarcopenia remains incomplete. Iron in the muscle is important for various metabolic functions including oxygen supply and electron transfer during energy production, yet these same chemical properties of iron may be deleterious to the muscle when either in excess or when biochemically unshackled (e.g., in ferroptosis), it can promote oxidative stress and induce inflammation. This review outlines the mechanisms leading to iron overload in muscle with aging and evaluates the evidence for the iron overload hypothesis of sarcopenia. Based on current evidence, studies are needed to: 1) determine the mechanisms leading to iron overload in skeletal muscle during aging; and 2) investigate whether skeletal muscles are functionally deficient in iron during aging leading to impairments in oxidative metabolism.

Relative quantification of progressive changes in healthy and dysferlin‐deficient mouse skeletal muscle proteomes

“…79 Macrophages are also essential in iron recycling by accumulating, metabolizing, and exporting it from damaged muscle fibers; defects in these pathways can lead to ferroptosis (reviewed in Alves et al and Wang et al). [80][81][82] Similarly, nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor for cell antioxidants and critical regulator of ferroptosis, is a potential therapeutic target for SM diseases. 80,83,84 Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted.…”

“…80,83,84 Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted. 80,81 Macrophages and other monocytes also secrete the anti-angiogenic protein thrombospondin-1 (TSP-1). 85,86 We note that monocytes are not the only source: cultured myotubes also secrete TSP-1, and dysferlin-deficient myotubes secrete significantly more TSP-1 than WT myotubes.…”

“…Unsurprisingly, macrophage infiltration is evident in the IPA as they are known to phagocytose damaged myofibers and deliver cytokines and growth factors to promote regeneration 79 . Macrophages are also essential in iron recycling by accumulating, metabolizing, and exporting it from damaged muscle fibers; defects in these pathways can lead to ferroptosis (reviewed in Alves et al and Wang et al) 80‐82 . Similarly, nuclear factor erythroid 2‐related factor 2 (NRF2), a transcription factor for cell antioxidants and critical regulator of ferroptosis, is a potential therapeutic target for SM diseases 80,83,84 .…”

“…Similarly, nuclear factor erythroid 2‐related factor 2 (NRF2), a transcription factor for cell antioxidants and critical regulator of ferroptosis, is a potential therapeutic target for SM diseases 80,83,84 . Iron homeostasis, ferroptosis, and mitochondrial dysfunction is widely studied in the context of exercised and aging SM, sarcopenia, and rhabdomyolysis; its exacerbation or potential unique role in dysferlinopathy should be vetted 80,81 …”

Drug‐related sarcopenia as a secondary sarcopenia

“…With aging, iron accumulates in various organs, and this iron overload leads to the production of ROS, which consume the ROS scavenging system, resulting in the collapse of redox homeostasis and the accumulation of lipid peroxide in the cell membrane, which induces cell death (ferroptosis, iron‐dependent non‐apoptotic cell death) 69 . It is hypothesized that this ferroptosis is also induced in skeletal muscle, resulting in age‐related sarcopenia 70 . In animal experiments and in humans, non‐heme iron accumulation in skeletal muscle occurs with aging and is associated with skeletal atrophy, 71–74 and in animal experiments excessive iron administration causes skeletal muscle atrophy 75 .…”