Muthu Periasamy

Beginning in early 2020, SARS-CoV-2, the virus responsible for COVID-19, spread across the world, giving rise to a global pandemic that impacted billions of people. Surprisingly, the United States was among one of the worst affected countries with over a million deaths. The purpose of this review is to discuss the impact of COVID-19 in the United States from the perspectives of government policies and the U.S. healthcare system. The emergence of multiple viral variants was at the center of sequential waves of infection in the U.S., resulting in increased number of cases, hospitalizations, and deaths along with associated mental health sequelae in the population. Lack of uniform policies at the local, state, and federal levels exacerbated the situation. These factors contributed to significant healthcare worker burnout. Furthermore, the disease caused higher morbidity and mortality rates in specific groups such as lower average socioeconomic status, rural and underserved communities, Native Americans and African Americans, and older age groups (65+ years). The lessons learned from this broad analysis highlight many inadequacies and challenges experienced in the U.S. during the pandemic. Here we propose several suggestions for healthcare and government responses in the event of future unanticipated healthcare crises.

A small peptide regulates muscle thermogenesis through interaction with the sarcoplasmic reticulum calcium ATPase.

Sarcolipin (SLN) is a regulator of sarco/endo plasmic reticulum Ca²⁺-ATPase (SERCA) pump and has been shown to be involved in muscle nonshivering thermogenesis (NST) and energy metabolism. Interestingly, SLN expression is significantly upregulated both during muscle development and in several disease states. However, the significance of altered SLN expression in muscle patho-physiology is not completely understood. We have previously shown that transgenic over-expression of SLN in skeletal muscle is not detrimental, and can promote oxidative metabolism and exercise capacity. In contrast, some studies have suggested that SLN upregulation in disease states is deleterious for muscle function and ablation of SLN can be beneficial. In this perspective article, we critically examine both published and some new data to determine the relevance of SLN expression to disease pathology. The new data presented in this paper show that SLN levels are induced in muscle during systemic bacterial (Salmonella) infection or lipopolysaccharides (LPS) treatment. We also present data showing that SLN expression is significantly upregulated in different types of muscular dystrophies including myotubular myopathy. These data taken together reveal that upregulation of SLN expression in muscle disease is progressive and increases with severity. Therefore, we suggest that increased SLN expression should not be viewed as the cause of the disease; rather, it is a compensatory response to meet the higher energy demand of the muscle. We interpret that higher SLN/SERCA ratio positively modulate cytosolic Ca²⁺ signaling pathways to promote mitochondrial biogenesis and oxidative metabolism to meet higher energy demand in muscle.

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.

Genetically engineered mouse models have been used to determine the role of sarcolipin (SLN) in muscle. However, few studies had difficulty in detecting SLN in FBV/N mice and questioned its relevance to muscle metabolism. It is known that genetic alteration of proteins in different inbred mice strains produce dissimilar functional outcome. Therefore, here we compared the expression of SLN and key proteins involved in Ca2+-handling and mitochondrial metabolism between FVB/N and C57BL/6J mouse strains. Data suggests that, SLN expression is less abundant in the skeletal muscles of FVB/N mice compared to C57BL/6J strain. The expression of Ca2+-transporters in the mitochondrial membranes, were also lower in FVB/N compared to C57BL/6J. Similarly the electron transport proteins in the mitochondria were less abundant in FVB/N mice which may contribute to differences in energy metabolism. Future studies using different mouse strains should take these differences into account while interpreting their data.

Obesity-associated metabolic illnesses are increasing at an alarming rate in Asian countries. A common feature observed in the Asian population is a higher incidence of abdominal obesity—the “skinny-fat” Asian syndrome. In this review, we critically evaluate the relative roles of genetics and environmental factors on fat distribution in Asian populations. While there is an upward trend in obesity among most Asian countries, it appears particularly conspicuous in Malaysia. We propose a novel theory, the Malaysian gene-environment multiplier hypothesis, which explains how ancestral variations in feast-and-famine cycles contribute to inherited genetic predispositions that, when acted on by modern-day stressors—most notably, urbanization, westernization, lifestyle changes, dietary transitions, cultural pressures, and stress—contribute to increased visceral adiposity in Asian populations. At present, the major determinants contributing to visceral adiposity in Asians are far from conclusive, but we seek to highlight critical areas for further research.

Thermogenesis in endotherms relies on both shivering and non-shivering thermogenesis (NST). The role of brown adipose tissue (BAT) in NST is well recognized, but the role of muscle-based NST has been contested. However, recent studies have provided substantial evidence for the importance of muscle-based NST in mammals. This review focuses primarily on the role of sarcoplasmic reticulum (SR) Ca ²⁺ -cycling in muscle NST; specifically, it will discuss recent data showing how uncoupling of sarcoendoplasmic reticulum calcium ATPase (SERCA) (inhibition of Ca ²⁺ transport but not ATP hydrolysis) by sarcolipin (SLN) results in futile SERCA pump activity, increased ATP hydrolysis and heat production contributing to muscle NST. It will also critically examine how activation of muscle NST can be an important factor in regulating metabolic rate and whole-body energy homeostasis. In this regard, SLN has emerged as a powerful signalling molecule to promote mitochondrial biogenesis and oxidative metabolism in muscle. Furthermore, we will discuss the functional interplay between BAT and muscle, especially with respect to how reduced BAT function in mammals could be compensated by muscle-based NST. Based on the existing data, we argue that SLN-mediated thermogenesis is an integral part of muscle NST and that muscle NST potentially contributed to the evolution of endothermy within the vertebrate clade. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

The Role of Sarcolipin in Muscle Non-shivering Thermogenesis