Hand grip strength is a widely used indicator of muscular fitness, and in older people reduced strength is a marker of frailty and physical decline. Previous research has also suggested that hand grip strength is associated with mortality risk, fracture risk, and even cardiovascular disease risk, although it’s not known whether these associations are causal or a reflection of underlying disease. 

Grip strength is highly heritable, and an international team of researchers has now for the first time identified 16 gene loci that influence muscle strength. Their findings could help to identify new biological pathways involved in muscle function and potentially lead to the development of targets and drugs for treating disorders characterized by muscle wasting or weakness.   

“While we have long suspected a role for genetics in the variation in muscle strength, these findings give the first insights into some of the specific genetic variants that underpin variation in strength,” commented Dr. Robert Scott, who co-led the study with Sara M. Willems, Ph.D., Nick Wareham, Ph.D., and colleagues from the MRC Epidemiology Unit at the University of Cambridge School of Clinical Medicine in the U.K. “These could be important steps toward identifying new treatments to prevent or treat muscle weakness.”

The team carried out large-scale genetic analysis of data from nearly 150,000 individuals in the U.K. Biobank and another 53,000 individuals from eight international studies. Many of the 16 gene loci variants that were found to be associated with hand grip strength are in chromosomal regions that harbor genes involved in skeletal muscle structure and function, neuronal maintenance, and signal transduction in the peripheral nervous system  and central nervous system (CNS). “Partitioned heritability analyses indicated significant tissue-specific enrichment of skeletal muscle, CNS, connective tissue and bone in the genome-wide grip strength results,” the authors write in their published paper (“Large-Scale GWAS Identifies Multiple Loci for Hand Grip Strength Providing Biological Insights into Muscular Fitness”) in Nature Communications. “We observed evidence of shared genetic aetiology of lean mass and grip strength, while pathway analyses indicated a role for genes involved in regulation of protein catabolism in the aetiology of grip strength.”

Although there was no evidence to support a casual association between muscle strength and either mortality risk or the risk of coronary heart disease or heart attack, a number of the grip strength–related chromosome regions contained genes implicated in myopathies, and in rare severe monogenic syndromes. The results also confirmed a causal link between genes linked with high muscle strength and reduced fracture risk. “… these results suggest that the determinants of muscular strength are shared with the determinants of fracture risk …,” the authors note.

“This work highlights the importance of muscle strength in the prevention of fractures and the complications which can often follow a fall,” added Prof. Wareham, director of the MRC Epidemiology unit.

The genome-wide analysis also found that a common variation in the ACVR2B gene, which encodes the principal receptor of myostatin and activin in skeletal muscle, was associated with variations in grip strength. The team says that this finding should support the ongoing development of drugs that target the pathway to help reverse muscle atrophy and improve physical function. Unfortunately for Novartis, last April its antibody candidate bimagrumab (BYM33), which targets the ACVR2B gene’s protein, ActRII, failed a Phase IIb/III study in patients with sporadic inclusion body myositis (sIBM). Meanwhile, Scholar Rock’s myostatin blocker SRK-015  is projected to start in clinical development during mid-2018 for treating spinal muscular atrophy.

“Further genetic and functional work to characterize these loci will elucidate new pathways involved in the regulation of muscle strength and inform the development of drugs to tackle muscle wasting and weakness,” the authors conclude in their paper.

The study results have generated valuable insight into causal pathways in muscle strength, the authors told GEN. “The next key step to take these findings one step closer to translation is to identify the specific genes that underlie these associations and their precise molecular consequences. By doing so, we may identify potential drug targets. There is evidence to suggest that drug targets with genetic support are more likely to be successful than those without, so these findings are a valuable first step in the drug discovery process.” The authors don’t envisage that the results will point to future screening programs, however. “While these variants identify important causal pathways in the etiology of muscle strength, the individual effect sizes of these variants is small, so we do not envisage that these variants will be used for screening.”

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