Latest Updates on Sarcopenia and Cachexia: Insights from the 17th Sarcopenia, Cachexia, and Wasting Disorders Conference

Abstract

The 17th Sarcopenia, Cachexia, and Wasting Disorders Conference, held from December 6 to 8, 2024, in Washington, DC, showcased groundbreaking advancements in understanding and managing muscle wasting conditions. Drawing on the lecture notes and presentations of internationally recognized experts who spoke at the meeting, this review highlights key insights and recent developments discussed during the conference. This review focuses on sarcopenia, cancer cachexia, and other wasting disorders linked to chronic diseases. Key discoveries included the identification of the Macroautophagy and YouTH Optimizer pathway in muscle regulation, the role of ectodysplasin A2 receptor-nuclear factor-κB-inducing kinase signaling in muscle atrophy, and the impact of mitochondrial dysfunction on systemic health. Advancements in diagnostic tools, including artificial intelligence-powered imaging and novel biomarkers, are transforming the detection and management of these conditions. Emerging therapeutic strategies, such as glucagon-like peptide 2-based treatments, selective androgen receptor modulators, and cytokine inhibitors, are reshaping the therapeutic landscape. The conference underscored the importance of precision medicine, integrating molecular insights with personalized care approaches, and emphasized multidisciplinary rehabilitation to optimize patient outcomes. The conference also highlighted promising clinical advancements, including the HIPGEN trial on placental-expanded stromal cells for muscle regeneration in hip fracture patients and the ponsegromab study targeting growth/differentiation factor-15 inhibition to mitigate cancer cachexia-associated muscle wasting. This review highlights the integration of basic science, innovative diagnostics, and clinical applications as a promising framework for addressing the complex challenges posed by muscle-wasting disorders. As the field progresses, these insights offer hope for improving the quality of life and survival of affected patients.

Keywords: Cachexia; Clinical trials as topic; Sarcopenia; Biomarkers.

Fig. 1

Molecular mechanisms underlying sarcopenia. Macroautophagy and YouTH Optimizer (Mytho) plays a dual role in muscle health. Acute Mytho knockdown during conditions such as starvation or cancer cachexia mitigates muscle atrophy and preserves muscle function. Prolonged knockdown leads to pathological hypertrophy due to chronic mechanistic target of rapamycin complex 1 (mTORC1) activation and reduced autophagosome formation, resulting in mitochondrial dysfunction. Activation of the ectodysplasin A2 receptor (EDA2R)-nuclear factor-κB-inducing kinase (NIK) pathway accelerates muscle degradation by upregulating E3 ubiquitin ligases atrogin-1 and muscle ring finger 1 (MuRF1), while HECD1 stabilizes sarcomeric proteins like nebulin and its dysregulation causes sarcomeric instability and nemaline myopathy.

Fig. 2

Mechanistic pathways involved in cancer cachexia. Elevated phosphoribosylpyrophosphate synthetase 1 (PRPS1) expression enhances xanthine oxidase activity, exacerbating purine metabolism dysregulation and muscle wasting. Ceramide (CER) species such as CER[16:0] and CER[24:1] derived from the de novo pathway impair protein synthesis and promote autophagy and apoptosis. Tumor-secreted cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 drive systemic alterations targeting adipose tissue lipolysis, fibrosis, and browning. Pharmacological interventions including CER synthesis inhibitors and phosphodiesterase (PDE) inhibitors like rolipram target mitochondrial dysfunction and restore cAMP response element-binding protein 1 (CREB1) activity.

Fig. 3

Therapeutic advances in addressing wasting disorders. Cytokine modulation strategies such as anti-interleukin (IL)-6 therapies and growth/differentiation factor-15 (GDF-15) inhibitors improve appetite, reverse anorexia, and preserve lean body mass. Mitochondria-targeting therapies such as SS-31 and manganese superoxide dismutase (MnSOD) overexpression stabilize mitochondrial function and promote muscle recovery. Appetite-stimulating agents like anamorelin paired with anti-catabolic therapies such as activin receptor 2B fused to the Fc region of immunoglobulin G (ActR2B-Fc) restore lean mass effectively. Multidisciplinary rehabilitation guided by 6-min walk test (6MWT) and functional independence measure optimizes patient care through team-based interventions.