Targeting Age-Dependent Functional and Metabolic Decline of Human Skeletal Muscle: The Geroprotective Role of Exercise, Myokine IL-6, and Vitamin D

Abstract

In the elderly, whole-body health largely relies on healthy skeletal muscle, which controls body stability, locomotion, and metabolic homeostasis. Age-related skeletal muscle structural/functional deterioration is associated with a higher risk of severe comorbid conditions and poorer outcomes, demanding major socioeconomic costs. Thus, the need for efficient so-called geroprotective strategies to improve resilience and ensure a good quality of life in older subjects is urgent. Skeletal muscle senescence and metabolic dysregulation share common cellular/intracellular mechanisms, potentially representing targets for intervention to preserve muscle integrity. Many factors converge in aging, and multifaceted approaches have been proposed as interventions, although they have often been inconclusive. Physical exercise can counteract aging and metabolic deficits, not only in maintaining tissue mass, but also by preserving tissue secretory function. Indeed, skeletal muscle is currently considered a proper secretory organ controlling distant organ functions through immunoactive regulatory small peptides called myokines. This review provides a current perspective on the main biomolecular mechanisms underlying age-dependent and metabolic deterioration of skeletal muscle, herein discussed as a secretory organ, the functional integrity of which largely depends on exercise and myokine release. In particular, muscle-derived interleukin (IL)-6 is discussed as a nutrient-level biosensor. Overall, exercise and vitamin D are addressed as optimal geroprotective strategies in view of their multi-target effects.

Vitamin C and E Treatment Blunts Sprint Interval Training–Induced Changes in Inflammatory Mediator-, Calcium-, and Mitochondria-Related Signaling in Recreationally Active Elderly Humans

“…Intriguingly, the expression of many inflammatory biomarkers associated with the low-grade inflammation in aging also increase in response to an exercise bout [ 7 ]. For instance, chronically elevated systemic levels of the cytokine IL-6 are associated with deteriorating muscle function in aging, whereas exercise-induced IL-6 released from skeletal muscle is associated with improved muscle health [ 8 , 9 ]. Along the same lines, the aging-related decline in muscle function has been associated with increased ROS levels; nevertheless, increased ROS production is observed during health promoting endurance exercise [ 9 , 10 ].…”

“…For instance, chronically elevated systemic levels of the cytokine IL-6 are associated with deteriorating muscle function in aging, whereas exercise-induced IL-6 released from skeletal muscle is associated with improved muscle health [ 8 , 9 ]. Along the same lines, the aging-related decline in muscle function has been associated with increased ROS levels; nevertheless, increased ROS production is observed during health promoting endurance exercise [ 9 , 10 ]. In fact, antioxidant treatment has been shown to reduce beneficial effects of endurance training [ 11 , 12 , 13 , 14 ], although other studies report no blunting of exercise-induced adaptations by antioxidant treatment [ 15 , 16 , 17 ].…”

Vitamin D Restores Skeletal Muscle Cell Remodeling and Myogenic Program: Potential Impact on Human Health

“…Supplementation, in fact, potentially represents the necessary intervention to reduce the risk of low vitamin D-induced pathologic status, including skeletal muscle diseases. Remarkably, it must be recalled that the good health of skeletal muscle promotes and supports a good general health status [ 11 , 12 ]. The required doses for supplementation likely depend on the need to respond to skeletal/extra-skeletal needs.…”

“…The biology and function of striated cells, despite low VDR expression, are exquisitely regulated by vitamin D, within either physiologic or pathologic contexts [ 6 , 7 , 8 , 9 , 10 ]. A wide spectrum of findings highlights the link between vitamin D deficiency and increase of skeletal muscle cell wasting, which turns into loss of tissue integrity/function, and, finally, ends in disease development [ 6 , 11 , 12 ]. Importantly, proper skeletal muscle cell remodeling is fully recognized as a key process to warrant tissue adaptation, recovery, and homeostasis [ 13 , 14 ], highly impacting general health status.…”

Histone deacetylase 5 regulates interleukin 6 secretion and insulin action in skeletal muscle

“…Exercise has been associated with enhanced phosphorylation and nuclear exclusion of HDAC5, leading to increased transcription of GLUT4 genes [ 10 , 17 ]. Furthermore, exercise is linked to anti-inflammatory, metabolic and regenerative benefits, likely driven by the release of skeletal muscle-derived secretory factors such as interleukin 6 (IL-6) [ [18] , [19] , [20] , [21] ]. IL-6 has insulin-like effects such as increasing glucose uptake and fatty acid oxidation in skeletal muscle [ 22 , 23 ].…”