Phosphate depletion in insulin-insensitive skeletal muscle drives AMPD activation and sarcopenia in chronic kidney disease

Andrés-Hernando, Ana; Cicerchi, Christina; García, Gabriela; Orlicky, David J.; Stenvinkel, Peter; Johnson, Richard J.; Lanaspa, Miguel A.

doi:10.1016/j.isci.2023.106355

Cited by 5 publications

(6 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The partial removal of kidney mass by surgery, also called subtotal nephrectomy, in mice and rats is a well-established animal model of CKD, and to date it is the most studied in regard to CKD-associated changes in skeletal muscle tissue . Subtotal nephrectomy in rodents induces skeletal muscle atrophy as indicated by a decrease in grip strength, running distance, and contractile force, as well as significant reductions in muscle mass [67][68][69][70][71][72][73][74]80,81,[92][93][94][95]. Furthermore, nephrectomized rodents show disturbances of protein metabolism in skeletal muscle, with increases in protein degradation and reductions in protein synthesis [68,[74][75][76][77][78][79][80].…”

Section: Traditional Factorsmentioning

confidence: 99%

“…It is known that insulin regulates sodium-dependent phosphate transport into cells [277,278] and that CKD is a state of insulin resistance [279]. A recent mechanistic study indicates that although serum phosphate is high in CKD, phosphate uptake into skeletal muscle cells is reduced, leading to reduced intracellular phosphate levels, which causes an activation of AMP deaminase (AMPD) and the transition of muscle fibers into a catabolic-prone state [92]. Studies in dialysis patients have shown that sarcopenia is associated with reduced serum phosphate levels [280] and that the dialysis process reduces intracellular phosphate levels [281], providing clinical evidence that low phosphate concentrations in skeletal muscle tissue rather than high phosphate concentrations in the circulation or the extracellular space might be the main culprit.…”

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

“…Studies in dialysis patients have shown that sarcopenia is associated with reduced serum phosphate levels [280] and that the dialysis process reduces intracellular phosphate levels [281], providing clinical evidence that low phosphate concentrations in skeletal muscle tissue rather than high phosphate concentrations in the circulation or the extracellular space might be the main culprit. Overall, it appears that intracellular phosphate could represent an "Achilles' heel" in muscle metabolism and function, and if altered might act as a potent driver of sarcopenia [92].…”

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

“…that the dialysis process reduces intracellular phosphate levels [281], providing clinical evidence that low phosphate concentrations in skeletal muscle tissue rather than high phosphate concentrations in the circulation or the extracellular space might be the main culprit. Overall, it appears that intracellular phosphate could represent an "Achilles' heel" in muscle metabolism and function, and if altered might act as a potent driver of sarcopenia [92]. This may include the cellular uptake of phosphate via specific transporters (PiT1/2), resulting in an increase in intracellular phosphate levels.…”

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

“…Furthermore, AMPD1 is an enzyme that converts adenosine monophosphate (AMP) into inosine monophosphate (IMP) and functions as a critical regulator of energy metabolism in myofibers. It has been shown that AMPD1 blockade protects from sarcopenia in nephrectomized mice [92].…”

Section: Pharmacological Interventions To Protect From Ckd-associated...mentioning

confidence: 99%

See 4 more Smart Citations

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

Heitman,

Alexander,

Faul

2024

IJMS

View full text Add to dashboard Cite

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

show abstract

Section: Traditional Factorsmentioning

confidence: 99%

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

Section: Phosphate and Sarcopeniamentioning

confidence: 99%

Section: Pharmacological Interventions To Protect From Ckd-associated...mentioning

confidence: 99%

See 3 more Smart Citations

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

Heitman,

Alexander,

Faul

2024

IJMS

View full text Add to dashboard Cite

show abstract

The recent development, application, and future prospects of muscle atrophy animal models

Zhang,

Hu,

Huang

et al. 2024

MedComm – Future Medicine

View full text Add to dashboard Cite

Muscle atrophy, characterized by the loss of muscle mass and function, is a hallmark of sarcopenia and cachexia, frequently associated with aging, malignant tumors, chronic heart failure, and malnutrition. Moreover, it poses significant challenges to human health, leading to increased frailty, reduced quality of life, and heightened mortality risks. Despite extensive research on sarcopenia and cachexia, consensus in their assessment remains elusive, with inconsistent conclusions regarding their molecular mechanisms. Muscle atrophy models are crucial tools for advancing research in this field. Currently, animal models of muscle atrophy used for clinical and basic scientific studies are induced through various methods, including aging, genetic editing, nutritional modification, exercise, chronic wasting diseases, and drug administration. Muscle atrophy models also include in vitro and small organism models. Despite their value, each of these models has certain limitations. This review focuses on the limitations and diverse applications of muscle atrophy models to understand sarcopenia and cachexia, and encourage their rational use in future research, therefore deepening the understanding of underlying pathophysiological mechanisms, and ultimately advancing the exploration of therapeutic strategies for sarcopenia and cachexia.

show abstract

Role of AMP deaminase in diabetic cardiomyopathy

Miura,

Kouzu,

Tanno

et al. 2024

Mol Cell Biochem

View full text Add to dashboard Cite

Phosphate depletion in insulin-insensitive skeletal muscle drives AMPD activation and sarcopenia in chronic kidney disease

Cited by 5 publications

References 78 publications

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

Skeletal Muscle Injury in Chronic Kidney Disease—From Histologic Changes to Molecular Mechanisms and to Novel Therapies

The recent development, application, and future prospects of muscle atrophy animal models

Role of AMP deaminase in diabetic cardiomyopathy

Contact Info

Product

Resources

About