Aging, sarcopenia and store-operated calcium entry

While overall bodily functions decrease with aging, the impact on some specific tissues produces life-changing consequences. For instance, skeletal muscle reduction in size and especially in function has tremendous negative implications for the individual, family and society.^1,2 The aging-related loss of muscle mass and strength leads to reduced quality of life, because muscle weakness itself is a co-morbidity that can lead to other pathological conditions. For example, a weaker elderly person is more prone to fall and suffer bone fractures, losing his/her independence and becoming anxious and depressed. Furthermore, difficulties in bone healing and long-term immobility can lead to the worsening or development of other chronic conditions. Less muscle also translates into metabolic diseases or imbalances that contribute to diabetes and cardiovascular diseases. For these reasons, sarcopenia has a very high price tag, with the world-wide related cost of sarcopenia and its consequences likely to be in the hundreds of billions of dollars.^1,2

Despite these astronomical monetary figures and astonishing consequences, sarcopenia has been mostly relegated to a second tier of relevance, since the heart and the brain still receive most of the individual, public and research attentions. As a matter of fact, as recently pointed out by the European and International Societies on Sarcopenia, a precise definition and diagnosis of sarcopenia are still not in place,^1,2 causing this condition to be underdiagnosed and not treated or poorly treated.

Recent studies point us in a direction that should be better explored. It can be argued that a key manifestation of aging in many tissues is the reduced activity of channels, transporters and co-transporters.³ Apparently, this is also true for skeletal muscles. Of particular interest for skeletal muscles, we have recently shown that the activity of store-operated calcium entry (SOCE) is significantly reduced in aged muscles and that such decrement in activity is linked to reduced contractile force and muscle power.^4,5 Notably, a very similar phenomenon of reduced SOCE has been identified in aged neuronal cells,⁶ conceivably a shared phenotype of aging excitable cells. While the exact roles of SOCE are still under investigation, the reduction of SOCE activity necessarily indicates that calcium refilling of the sarcoplasmic reticulum (SR) will be diminished upon repetitive contraction-relaxation cycles.⁵ If this situation becomes chronic, the SR would naturally have less calcium available to be released for contractions, ultimately translating into less contractile force, which, when coupled with the aging-related shift of faster into slower myosin/myosin light chain isoforms,⁷ unequivocally results in decreased muscle power. These complex modifications might help explain the puzzling fact that atrophy alone can only explain a part of the totality of power loss in aged muscles^8,9 as well as open the doors of our scientific inquiry to new signaling pathways that might contribute to the complex phenotype of the aged muscle.^8–13

But this is not the entire tale of SOCE in aging muscles. Recent studies in our lab suggest that SOCE and extracellular calcium entry might also play roles in modulating muscle myogenic differentiation as well as muscle adaptation to stress, such as heat shock. Is it possible that reduced SOCE during aging works like a double-edged sword by altering both gene regulation and contractile force?

If future studies confirm such a possibility, SOCE will stand as a potential biomarker of muscle weakness during aging as well as a key target for therapeutical interventions for prevention of sarcopenia, muscle myopathies and other diseases where muscle wasting and weakness are at center stage.

Irrespective of the outcome of these studies, perhaps it is time that skeletal muscles receive the attention they deserve, or at least the attention that matches their fundamental roles in health and disease during development, growth and aging.

Comment on: Thornton AM, et al. Aging. 2011;3:621–634. doi: 10.18632/aging.100335.