The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) pump: a potential target for intervention in aging and skeletal muscle pathologies

As a key regulator of cellular calcium homeostasis, the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump acts to transport calcium ions from the cytosol back to the sarcoplasmic reticulum (SR) following muscle contraction. SERCA function is closely associated with muscle health and function, and SERCA activity is susceptible to muscle pathogenesis. For example, it has been well reported that pathological conditions associated with aging, neurodegeneration, and muscular dystrophy (MD) significantly depress SERCA function with the potential to impair intracellular calcium homeostasis and further contribute to muscle atrophy and weakness. As a result, targeting SERCA activity has attracted attention as a therapeutical method for the treatment of muscle pathologies. The interventions include activation of SERCA activity and genetic overexpression of SERCA. This review will focus on SERCA function and regulation mechanisms and describe how those mechanisms are affected under muscle pathological conditions including elevated oxidative stress induced by aging, muscle disease, or neuromuscular disorders. We also discuss the current progress and therapeutic approaches to targeting SERCA in vivo.

Glucose intolerance in aging is mediated by the Gpcpd1-GPC metabolic axis

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, muscle mediated metabolic homeostasis is perturbed, contributing to the onset of multiple chronic diseases. Our knowledge on the mechanisms responsible for this age-related perturbation is limited, as it is difficult to distinguish between correlation and causality of molecular changes in muscle aging. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is a highly abundant muscle enzyme responsible for the hydrolysis of the lipid glycerophosphocholine (GPC). The physiological function of GPCPD1 remained largely unknown. Here, we report that the GPCPD1-GPC metabolic pathway is dramatically perturbed in the aged muscle. Muscle-specific inactivation of Gpcpd1 resulted in severely affected glucose metabolism, without affecting muscle development. This pathology was muscle specific and did not occur in white fat-, brown fat- and liver-specific Gpcpd1 deficient mice. Moreover, in the muscle specific mutant mice, glucose intolerance was markedly accelerated under high sugar and high fat diet. Mechanistically, Gpcpd1 deficiency results in accumulation of GPC, without any other significant changes in the global lipidome. This causes an aged-like transcriptomic signature in young Gpcpd1 deficient muscles, changes in myofiber osmolarity, and impaired insulin signaling. Finally, we report that GPC levels are markedly perturbed in muscles from both aged humans and patients with Type 2 diabetes. These results identify the GPCPD1-GPC metabolic pathway as critical to muscle aging and age-associated glucose intolerance.

Regional Differences in the Diagnosis of Sarcopenia in Older People in Brazil

Introduction: Sarcopenia is a prevalent condition, and that is strongly associated with morbimortality outcomes. The optimal way to diagnose sarcopenia is currently a matter of debate. Despite evidence suggesting differences in body composition and physical performance of individuals from different regions, the diagnosis of sarcopenia in Brazil is still conducted using cutoff values established by international consensus. Therefore, the objective of this study was to establish cutoff values for appendicular muscle mass and muscle strength in a population of elderly outpatients with cardiovascular diseases from the city of São Paulo, using this data to compare populations with sarcopenia diagnosed in Brazil with individuals diagnosed using the European consensus values. Materials and Methods: This was a cross-sectional analysis including 502 older individuals from the SARCOS-Brazil study. All subjects underwent densitometry to assess muscle mass and measure strength using a manual dynamometer. The cutoff values for the SARCOS-Brazil criteria were obtained from the 25th percentile of each variable. Results and Discussion: There was no difference in the prevalence of muscle weakness using the two methods (180 patients, 35.9% of the sample). However, a difference was observed concerning low muscle mass. According to the European criteria, a total of 215 older individuals (42.8%) had low muscle mass and 123 (24.5%) according to the SARCOS-Brazil criteria. The prevalence of sarcopenia was 20.3% according to European criteria versus 13.7% according to the SARCOS-Brazil criteria. The kappa coefficient was 0.79. Conclusion: This study suggests that weakness and muscle mass can, in isolation, predict variables related to past vulnerability outcomes, as well as highlights the possibility of using regional cutoff values for the diagnosis of sarcopenia. Keywords: Sarcopenia; Aging; Muscle mass; Muscle strength

Skeletal Muscle Specific Calpastatin Overexpression Mitigates Muscle Weakness in Aging and Extends Lifespan

Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin, an endogenous inhibitor of calpain (CalpOX), solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed 4 groups of mice (age in months): (1) young wild type (5.71±0.43) (WT); (2) young CalpOX (5.6±0.5); (3) old WT (25.81±0.56); and (4) old CalpOX (25.91±0.60) for diaphragm and limb muscle (extensor digitorum longus, EDL) force frequency relations. Aging significantly reduced diaphragm and EDL peak force in old WT mice, and decreased the force-time integral during a fatiguing protocol by 48% and 23% in aged WT diaphragm and EDL, respectively. In contrast, we found that CalpOX mice had significantly increased diaphragm and EDL peak force in old mice, similar to that observed in young mice. The impact of aging on the force-time integral during a fatiguing protocol was abolished in the diaphragm and EDL of old CalpOX animals. Surprisingly, we found that CalpOX had a significant impact on longevity, increasing median survival from 20.55 months in WT mice to 24 months in CalpOX mice (p = 0.0006).

An age-downregulated ribosomal RpS28 protein variant regulates the muscle proteome

Recent evidence indicates that the composition of the ribosome is heterogeneous and that multiple types of specialized ribosomes regulate the synthesis of specific protein subsets. In Drosophila, we find that expression of the ribosomal RpS28 protein variants RpS28a and RpS28-like preferentially occurs in the germline, a tissue resistant to aging, and that it significantly declines in skeletal muscle during aging. Muscle-specific overexpression of RpS28a at levels similar to those seen in the germline decreases early mortality and promotes the synthesis of a subset of proteins with known anti-aging roles, some of which have preferential expression in the germline. These findings indicate a contribution of specialized ribosomal proteins to the regulation of the muscle proteome during aging.

Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle

Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.

The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function

Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults

Sarcopenia, defined as age-related reduction in muscle mass, strength, and physical performance, is associated with other age-related health conditions such as osteoporosis, osteosarcopenia, sarcopenic obesity, physical frailty, and cachexia. From a healthy aging perspective, lifestyle interventions that may help overcome characteristics and associated comorbidities of sarcopenia are clinically important. One possible intervention is creatine supplementation (CR). Accumulating research over the past few decades shows that CR, primarily when combined with resistance training (RT), has favourable effects on aging muscle, bone and fat mass, muscle and bone strength, and tasks of physical performance in healthy older adults. However, research is very limited regarding the efficacy of CR in older adults with sarcopenia or osteoporosis and no research exists in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia. Therefore, the purpose of this narrative review is (1) to evaluate and summarize current research involving CR, with and without RT, on properties of muscle and bone in older adults and (2) to provide a rationale and justification for future research involving CR in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia.

Molecular Basis for the Therapeutic Effects of Exercise on Mitochondrial Defects

Mitochondrial dysfunction is common to many organ system disorders, including skeletal muscle. Aging muscle and diseases of muscle are often accompanied by defective mitochondrial ATP production. This manuscript will focus on the pre-clinical evidence supporting the use of regular exercise to improve defective mitochondrial metabolism and function in skeletal muscle, through the stimulation of mitochondrial turnover. Examples from aging muscle, muscle-specific mutations and cancer cachexia will be discussed. We will also examine the effects of exercise on the important mitochondrial regulators PGC-1α, and Parkin, and summarize the effects of exercise to reverse mitochondrial dysfunction (e.g., ROS production, apoptotic susceptibility, cardiolipin synthesis) in muscle pathology. This paper will illustrate the breadth and benefits of exercise to serve as “mitochondrial medicine” with age and disease.